Response to e letter ID jmedgenet el; 2826 by Refaeli et al., dated
June14, 2016
A considerable amount of literature on the role of podocalyxin-like
(PODXL) protein in normal mammalian kidney functions and to a lesser
extent in mouse brain development is available. We agree that these
studies particularly, "Anuria, Omphalocele, and Perinatal Lethality in
Mice Lacking the Cd34-Related Protein Podocalyxin" by Doyonnas et...
Response to e letter ID jmedgenet el; 2826 by Refaeli et al., dated
June14, 2016
A considerable amount of literature on the role of podocalyxin-like
(PODXL) protein in normal mammalian kidney functions and to a lesser
extent in mouse brain development is available. We agree that these
studies particularly, "Anuria, Omphalocele, and Perinatal Lethality in
Mice Lacking the Cd34-Related Protein Podocalyxin" by Doyonnas et al (1)
and "Podocalyxin is a Novel Polysialylated Neural Adhesion Protein with
Multiple Roles in Neural Development and Synapse Formation" by Vitureira
et al (2) using podxl -/- mouse embryos and newborns have unequivocally
demonstrated the role of this gene in renal function and brain development
respectively. Doyonnas et al., (1) in their paper do mention that i)
anuria and renal failure is evidenced only postnatally as there is
possible maternal clearance in the embryos; ii) there is no evidence of
extensive proteinuria, which is characteristic of leaky podocyte
filtration in human nephrotic syndromes; and iii) more importantly, that
there were no developmental anomalies in the hematopoietic and vascular
endothelial cells which also express high levels of podocalyxin. The last
observation, authors hypothesized, may have been enabled through
functional compensation by other sialomucins such as CD34. Data on the
status of neural development in their newborn mice with identical genetic
background, which would have proved the effect of podxl deficiency in
these two vital processes is however missing in their paper. Overall, the
results from these mouse studies suggest that i) podxl protein is almost
ubiquitous in expression, multifunctional, may have varying interacting
partners and that functional/genetic redundancy exists.
In our opinion, these features of PODXL are exactly what the two mutation
studies in this gene one on autosomal dominant familial focal and
segmental glomerulosclerosis (FSGS) (3) and our study on autosomal
recessive juvenile parkinsonism (4) reflect. This is not unexpected
considering the different genetic backgrounds in different families.
Notably, in the paper by Barua et al, (3) i) the incomplete penetrance of
the private variant p.L442R (i.e., one individual carrying the mutation
but asymptomatic even at 53 years of age); ii) varying age of onset
ranging from early teenage to adulthood but developing end stage renal
disease between 2nd to 6th decade of life; iii) varying disease severity
across affected individuals in the family but certainly not post-
natal/newborn mortality (unlike in mice); and iv) rarity of mutations in
PODXL gene in 176 additional FSGS families; together with mutant PODXL
protein characterization in vitro which showed that the index mutation
results in dimerization but does not alter protein stability,
extracellular domain glycosylation, cell surface expression, global
subcellular localisation and interactions with its intracellular binding
partner ezrin are all the features of PODXL gene that need to be kept in
mind prior to assigning it an indispensable role in kidney function and
survival in humans. It is indeed appropriate that Barua et al (3) conclude
that rare variants with low statistical genetic evidence such as observed
in their study do not contribute significantly to glomerular disease in
humans.
Based on these observations, it is not unlikely that the index family
with ARJP with homozygous mutations predicted to result in loss of protein
did not manifest any symptoms of FSGS or any other kidney dysfunction,
based on the data of last clinical examination in 2009. As for the two
other concerns of Refaeli et al on the index mutation being unlikely of
germline origin and NGS errors, both can be disregarded as both the
parents are heterozygous for the index mutation (data not shown), and all
informative NGS data are validated by Sanger sequencing. Further, their
concern that mutations identified in unrelated PD cohort are just common
protein altering variants is also ruled out as these were not observed in
either our population or reported in any publically available large
databases and therefore, were functionally characterized in our study. As
for the demonstration of absence of PODXL RNA or protein, we have not been
able to do that due to non-availability of tissues. It may please be noted
that in the absence of clinical indications, it is difficult to obtain
ethical committee clearance for collection of target tissues.
In summary, from careful interpretation of the findings in the above
mentioned studies as well as abundant data in literature [for eg. See Liao
and Zhang, PNAS, 2008 (5)], it is clear that there are notable
differences between mice and humans in i) the developmental phenomena; ii)
functional compensatory mechanisms/genetic redundancy; iii) gene-gene
interactions; iv) tissue specific transcript expression etc. Though
experimental evidence for most of these aspects with specific reference to
PODXL is currently unavailable, such differences may be believed to be
useful to explain pleiotropy in PODXL [for eg. similar to that documented
in cystic fibrosis (6)], possible tolerance to null alleles enabling
apparently normal kidney function as witnessed in the ARJP family in our
study (4) and comparatively late age of onset of FSGS, incomplete
penetrance of the gene mutation etc. (3) and several other associated
features.
Finally, we would like to thank Rafaeli et al for their interest in our
work and giving us an opportunity to highlight some of the differences
which may exist between humans and mice in general and for role of
podocalyxin in particular. We firmly believe that findings from animal
models of human diseases are powerful tools but are not always true
representatives for understanding complete human health and disease
biology. Additional data as and when available on PODXL associated human
phenotypes would be most insightful for our enhanced understanding of the
role of PODXL in humans.
References:
1. Doyonnas R, Kershaw DB, Duhme C, et al. Anuria, omphalocele, and
perinatal lethality in mice lacking the CD34-related protein podocalyxin.
J Exp Med 2001;194(1):13-27.
2. Vitureira N, Andres R, Perez-Martinez E, et al. Podocalyxin is a novel
polysialylated neural adhesion protein with multiple roles in neural
development and synapse formation. PLoS One 2010;5(8):e12003.?
3. Barua M, Shieh E, Schlondorff J, et al. Exome sequencing and in vitro
studies identified podocalyxin as a candidate gene for focal and segmental
glomerulosclerosis. Kidney Int 2014;85(1):124-33.
4. Sudhaman S, Prasad K, Behari M, et al. Discovery of a frameshift
mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion
molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med
Genet 2016; 53(7):450-6.
5. Liao B, Zhang J. Null mutations in human and mouse orthologs frequently
result in different phenotypes. PNAS 2008;105(19):6987-92.
6. Sing C, Risser D, Howatt W, Erickson R. Phenotypic heterogeneity in
cystic fibrosis. American Journal of Medical Genetics 1982;13:179-195.
Conflict of Interest:
None declared
Dr. Sumedha Sudhaman1 Prof. Kameshwar Prasad2 Prof. Madhuri Behari2
Dr. Uday B Muthane3 Dr. Ramesh C Juyal4 Prof. BK Thelma1 1Department of
Genetics, University of Delhi South Campus, New Delhi, India 2Department
of Neurology, All India Institute of Medical Sciences, New Delhi, India
3Parkinson's and Ageing Research Foundation, Bengaluru, Karnataka, India
4Regional Center for Biotechnology, Faridabad, Haryana, India
Sudhaman, et al. Discovery of a frameshift mutation in podocalyxin-
like (PODXL) gene, coding for a neural adhesion molecule, as causal for
autosomal-recessive juvenile Parkinsonism. J Med Genet. 0:1-7, 2016.
In the February 2016 edition of the Journal of Medical Genetics,
Sudhaman et al(1) report the identification of a PODXL variant
(c.89_90insGTCGCCCC) as the causative mutation in an Indian fam...
Sudhaman, et al. Discovery of a frameshift mutation in podocalyxin-
like (PODXL) gene, coding for a neural adhesion molecule, as causal for
autosomal-recessive juvenile Parkinsonism. J Med Genet. 0:1-7, 2016.
In the February 2016 edition of the Journal of Medical Genetics,
Sudhaman et al(1) report the identification of a PODXL variant
(c.89_90insGTCGCCCC) as the causative mutation in an Indian family with
autosomal recessive juvenile parkinsonism (ARJP). They further claim that
the insertion mutation in exon 1 results in a frameshift and loss of
podocalyxin protein expression in disease-afflicted family members
(homozygous individuals). They subsequently identify three novel PODXL
variants (heterozygous missense mutations) in unrelated individuals with
Parkinson's disease (PD).
As the authors note in their report, we previously demonstrated that
Podxl-deficient neurons (derived from Podxl-/- mouse embryos) display
defective neurite branching in vitro(2). Thus, we concur with Sudhaman et
al that the loss of PODXL expression from neurons or other functionally
disruptive mutations in PODXL may alter neurite growth and branching.
However, we have also shown that germline loss of Podxl in mice leads to
anuria and death less than 24 hours after birth(3). This lethal Podxl-null
phenotype is the result of a failure to produce podocyte foot processes
and filtration slits during kidney morphogenesis. In 2014, Barua et al(4)
reported a missense mutation in an exon encoding the transmembrane domain
of podocalyxin as a cause for autosomal dominant focal segmental
glomerulosclerosis (FSGS). Affected individuals presented with renal
symptoms in the second decade of life eventually progressing to end-stage
renal disease requiring dialysis or renal transplant(4). Thus, these
previous studies in human and mouse have underscored the indispensible
role for PODXL in normal mammalian kidney function and survival.
From that vantage point we find it difficult to reconcile the late
age of onset and phenotype observed in the Sudhaman manuscript. The
phenotype was restricted to Parkinsonian symptoms with an onset of 17, 16
and 13 years. The fact that these individuals displayed normal birth and
adolescent milestones prior to disease onset, and specifically normal
renal function at age of examination (22, 20 and 17 years, respectively),
is incompatible with the known function for this protein in kidney and
leaves us skeptical of the conclusion that the ARJP-afflicted individuals
in the family documented in the Sudhaman manuscript are indeed germline
and functionally null mutations in PODXL.
We note that the DNA sequence reported in the Sudhaman et al
manuscript maps to a known in-frame Pro-Ser expansion polymorphism
(rs759639123) (or similar dbSNPs) following Ser31 (duplication of GTCGCC).
As this sequence is particularly GC rich, it is prone to sequencing errors
that could have been misinterpreted as a null mutation.
Although the authors suggested the possibility of nonsense mediated
decay, they did not provide any data suggesting complete absence of PODXL
RNA or podocalyxin protein, further raising concern as to whether the
variant generates a truly null allele. While this locus and polymorphism
could well be linked to the observed ARJP phenotype we would argue that,
based on the published literature and the known mouse Podxl null
phenotypes, it is unlikely that these afflicted individuals are carrying
two germline null alleles.
We are also concerned with the authors' interpretation of the
replication study, which involved screening for any PODXL variants in 280
PD patients. Due to the high frequency of rare protein-altering variants
in the human genome, there is a distinct possibility that these missense
PODXL variants are not directly associated with PD. The three reported
PODXL rare variant carriers consist of one young-onset, one old-onset and
one familial PD patient where the variant functionality and segregation
studies were not described in the report. The presence of such variants,
in the absence of confirmatory biochemical or phenotypic evidence, should
not be interpreted as causal. Furthermore, two (p.294Q and p.S373N) of the
three variants display poor evolutionary conservation and exhibit
discordant amino acids between human and rodent proteins.
Finally, because podocalyxin is highly expressed by vascular
endothelia and kidney podocytes, immunohistologic evaluation of
podocalyxin expression on vessel-containing skin biopsies (or better
still, renal biopsies) from the ARJP-afflicted patients described in the
manuscript would likely resolve this issue. In lieu of that data, we would
argue that the main conclusions of this manuscript remain speculative.
Respectfully,
Mr. Ido Refaeli1
Dr. Michael R. Hughes1
Mr. Moses Lee2
Prof. Murim Choi2
Prof. Kelly M. McNagny1
1Department of Medical Genetics, University of British Columbia,
Vancouver, BC CANADA and 2Department of Biomedical Sciences, Seoul
National University, Seoul, REPUBLIC OF KOREA
REFERENCES
1. Sudhaman S, Prasad K, Behari M, et al. Discovery of a frameshift
mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion
molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med
Genet 2016.
2. Vitureira N, Andres R, Perez-Martinez E, et al. Podocalyxin is a
novel polysialylated neural adhesion protein with multiple roles in neural
development and synapse formation. PLoS One 2010;5(8):e12003.
3. Doyonnas R, Kershaw DB, Duhme C, et al. Anuria, omphalocele, and
perinatal lethality in mice lacking the CD34-related protein podocalyxin.
J Exp Med 2001;194(1):13-27.
4. Barua M, Shieh E, Schlondorff J, et al. Exome sequencing and in
vitro studies identified podocalyxin as a candidate gene for focal and
segmental glomerulosclerosis. Kidney Int 2014;85(1):124-33.
I just read the articles on SMA1, SMA2, SMA3. I felt it important to
tell you of my son, born 1/26/70. When I took him to his first checkup at
3 months old, I voiced my concern for his floppy head. Again at 6 months
old, when he couldn't sit up, roll over, kick against resistance.
Finally, the Pediatrician agreed to get an appointment with Yale Hospital
in CT at 8 mos. The biopsy was shown to be SMA 1. We weren't given...
I just read the articles on SMA1, SMA2, SMA3. I felt it important to
tell you of my son, born 1/26/70. When I took him to his first checkup at
3 months old, I voiced my concern for his floppy head. Again at 6 months
old, when he couldn't sit up, roll over, kick against resistance.
Finally, the Pediatrician agreed to get an appointment with Yale Hospital
in CT at 8 mos. The biopsy was shown to be SMA 1. We weren't given any
chance of survival. He was subsequently re-diagnosed at 3 years old, and
again the results were, SMA1. He is now 46 years old. Graduated UCONN with
honors and is still living in Litchfield CT. He is not on a ventilator but
uses a bi-pap, 6 to 8% lung capacity. We have been told over and over
there is no medication and there is no trials he could be involved with.
However, with the social media being his way to communicate with the mass
population he has discovered the Salbutamol available now through a client
with SMA2. She has given us hope that this new drug will give him even
the slightest increase in strength to keep the two fingers he uses to
control his fiber optic wheelchair. Unfortunately its too expensive. It is
heartbreaking to come so close to possibly gaining enough strength to stay
mobile. If there is any possible way he could be helpful to your programs
via computer please let us know. Respectfully,
June Lajoie Strada
I wish to thank the authors of the review (1) of my book on
scientific writing (2). Here are further free documents for authors: the
Micro-Article, described in the book, is a template allowing to identify
the main discovery before starting to write an article (3). Writing a
Review Article in 7 Steps is a short note providing guidelines to write a
review or a book chapter (4). This note proposes in particular a
convenie...
I wish to thank the authors of the review (1) of my book on
scientific writing (2). Here are further free documents for authors: the
Micro-Article, described in the book, is a template allowing to identify
the main discovery before starting to write an article (3). Writing a
Review Article in 7 Steps is a short note providing guidelines to write a
review or a book chapter (4). This note proposes in particular a
convenient method to build the abstract by writing first short conclusions
at the end of the manuscript sections. The golden rules of scientific
publishing are outlined in a brief presentation (5). Scientific Writing
and Communication is the presentation of my workshop given to Masters,
PhDs and research scientists (6).
References: 1. J. Med. Genet. 2015 0:jmedgenet-2015-103182v1-
jmedgenet-2015-103182; doi:10.1136/jmedgenet-2015-103182, 2. Scientific
Writing for Impact Factor Journals. Nova Science Publishers. 2013.
https://www.novapublishers.com/catalog/product_info.php?products_id=42211,
3. Micro-article. http://fr.slideshare.net/lichtfouse/micro-arten, 4.
Writing a review article in 7 steps.
http://fr.slideshare.net/lichtfouse/writea-review, 5.
http://fr.slideshare.net/lichtfouse/scientific-writing-for-impact-factor-
journals, 6. Scientific Writing and Communication.
http://fr.slideshare.net/lichtfouse/scientific-writing-and-communication
I wish to thank the authors of the review (1) of my book on
scientific writing (2). Here are further free documents for authors: the
Micro-Article, described in the book, is a template allowing to identify
the main discovery before starting to write an article (3). Writing a
Review Article in 7 Steps is a short note providing guidelines to write a
review or a book chapter (4). This note proposes in particular a
convenie...
I wish to thank the authors of the review (1) of my book on
scientific writing (2). Here are further free documents for authors: the
Micro-Article, described in the book, is a template allowing to identify
the main discovery before starting to write an article (3). Writing a
Review Article in 7 Steps is a short note providing guidelines to write a
review or a book chapter (4). This note proposes in particular a
convenient method to build the abstract by writing first short conclusions
at the end of the manuscript sections. The golden rules of scientific
publishing are outlined in a brief presentation (5). Scientific Writing
and Communication is the presentation of my workshop given to Masters,
PhDs and research scientists (6).
References: 1. J. Med. Genet. 2015 0:jmedgenet-2015-103182v1-
jmedgenet-2015-103182; doi:10.1136/jmedgenet-2015-103182, 2. Scientific
Writing for Impact Factor Journals. Nova Science Publishers. 2013.
https://www.novapublishers.com/catalog/product_info.php?products_id=42211,
3. Micro-article. http://fr.slideshare.net/lichtfouse/micro-arten, 4.
Writing a review article in 7 steps.
http://fr.slideshare.net/lichtfouse/writea-review, 5.
http://fr.slideshare.net/lichtfouse/scientific-writing-for-impact-factor-
journals, 6. Scientific Writing and Communication.
http://fr.slideshare.net/lichtfouse/scientific-writing-and-communication
Letter to Editor
Shaheen et al. 1 recently reported a homozygous 5 bps deletion mutation
(c.1299_1303delTAAG; p.Phe433Leufs*6) in the human polo-like kinase 4
(PLK4,MIM 605031) gene and proposed that it is a compelling candidate for
primordial dwarfism (PD). Autozygosity mapping and LOD score, method of
estimating linkage distances, are adopted for the novel locus
identification. Candidate gene hunting among 144 in the r...
Letter to Editor
Shaheen et al. 1 recently reported a homozygous 5 bps deletion mutation
(c.1299_1303delTAAG; p.Phe433Leufs*6) in the human polo-like kinase 4
(PLK4,MIM 605031) gene and proposed that it is a compelling candidate for
primordial dwarfism (PD). Autozygosity mapping and LOD score, method of
estimating linkage distances, are adopted for the novel locus
identification. Candidate gene hunting among 144 in the region is based on
filtering through ToppGene suite 2. Mutation screening through Sanger
sequencing of PLK4 gene is only based on ToppGene suite ranking. In this
study authors have not mentioned how many and which samples were selected
for genotyping and linkage analysis so the predicted maximum LOD score
cannot be calculated. Maximum multipoint LOD score (2.5) obtained by the
authors is quite lower than the established threshold values (3.0). In
article it has been stated that all PD genes in training set in comparison
to all 144 genes of the locus in test set were enrolled in ToppGene
candidate prioritization. These genes lists must be provided along with
test parameters. In our opinion these informations are essential for data
reproducibility and validation.
Only PLK4 gene has been selected for Sanger sequencing but The candidate
region (Chr4:112904466-129392060, GRCh37/hg19) includes some of the well-
known syndromes characterized by autosomal recessive intellectual
disabilities, microcephaly, short stature, and overlapping phenotypes.
Alazami syndrome caused by mutations in LARP7, autosomal recessive type 1
mental retardation caused by mutations in PRSS12, Bardet-Biedl syndrome
caused by mutations in BBS7 and BBS12, Van Maldergem syndrome 2 caused by
mutations in FAT4, neuronal ceroid lipofuscinosis 7 caused by mutations in
MFSD8, a multisystem disorder including brain function caused by mutation
in SCLT1, as well as genes involved in mitosis and brain development e.g.
MAD2L1, FGF2, INTU, have not been discussed throughout the manuscript.
Furthermore, chromatograms for obligate carriers have not been presented
nor the Saudi population screening for minor allele frequency has been
performed. Similarly a homozygous variant (NM_014264.4, c.1556G>C;
p.Trp519Ser) reported in ESP6500 (http://evs.gs.washington.edu/EVS/)
alters a highly conserved amino acid of PLK4 however it has not been
assigned to any of primordial dwarfism phenotype and not discussed by the
authors. In fact, phenotypic overlaps among the study mutants and the
above syndromes would be of far more value instead of paying an
exaggerated attention to PLK4 biology.
References
1 Shaheen R, Al Tala S, Almoisheer A et al. Mutation in PLK4,
encoding a master regulator of centriole formation, defines a novel locus
for primordial dwarfism. Journal of medical genetics 2014.
2 Chen J, Bardes EE, Aronow BJ et al. ToppGene Suite for gene list
enrichment analysis and candidate gene prioritization. Nucleic acids
research 2009; 37: W305-11.
I have read all the respective article and I agreed to most of the
findings. Recently, our group has been working with metabolomics towards
lipodystropy and we did found similar findings. Recently it has been
reported (Abael et al., 2010) that the changes in local thyroid hormone
(TH) metabolism may occur in areas with lipoatrophy. These changes could
be because of different molecular mechanisms (for example; levels of...
I have read all the respective article and I agreed to most of the
findings. Recently, our group has been working with metabolomics towards
lipodystropy and we did found similar findings. Recently it has been
reported (Abael et al., 2010) that the changes in local thyroid hormone
(TH) metabolism may occur in areas with lipoatrophy. These changes could
be because of different molecular mechanisms (for example; levels of
monocarboxylate transporter 8 and iodothyronine deiodinases). Recently, it
has been reported that the prelamin A accumulating mesenchymal stem cells
(hMSCs) have a premature aging phenotype which affects their functional
competence in vivo. The combination of prelamin A accumulation and stress
conditions enhance the aging phenotype by dysregulating the activity of
the octamer binding protein Oct-1(Infante et al., 2014). There is a need
to evaluate Oct-1 in type 2 familial partial lipodystrophy. Stress could
be in the form of hypoxia and oxygen concentration and PO2 is documented
to be involved in the activity of nucleoside reverse transcriptase
inhibitors (NRTIs) to characterised the metabolic effect on the targeted
adipose tissues (Gentil et al., 2006). There could be a relation between
hypoxia inducible factors (HIF1 & HIF2) to be defined for
lipodystrophy.
Hypoxia Inducible Factor 1 (HIF-1) was firstly identified to be a
nuclear factor involved in activation of gene expression under the
response of reduced cellular O2 during Erythropoietin expression and
regulation (Semenza & Wang, 1992). Following this invention, HIF-1 was
reported to be involved in expression and regulation of Vascular
Endothelial Growth Factor (VEGF), glycolytic enzymes, nitric oxide
synthetase and glucose transporter 1 (Glut 1) (Wenger & Gassmann.
1997; Semenza, 1998). Structurally, HIF-1 is a heterodimer composed of two
basic helix-loop-helix PAS domains (bHLH-PAS) protein, called HIF-1? and
HIF-1? subunits (Wang et al., 1995).
Tian and colleagues (Tian et al., 1997) identified a novel bHLH-PAS
protein called Endothelial PAS domain protein (EPAS1) with 48% sequence
similarity with HIF-1 ?. Further studies termed it as HIF-like factor
(HLF) (Ema et al., 1997) followed by HIF-related factor (HRF) (Flamme et
al., 1997) followed by current name given to this factor to be HIF-2
(Wenger & Gassmann, 1997). Recently, it has been shown that HIF-2 ?
forms a functional heterodimer with HIF-1?, resulting in the HIF-2 complex
and this complex has been found to bind the same hypoxia response element
(HRE) of Epo and VEGF gene to which HIF-1 complex binds. Both of these HRE
and bindings (binding of HIF-1 and HIF-2 complex) are activated under
hypoxic conditions (Tian et al., 1997, Ema et al., 1997).
The role of HIF-2 as compared to HIF-1 has been much less studied.
Patel and colleagues (Patel et al., 2008) reported HIF-2 complex to be
more tissue specific than HIF-1 by suggesting its response to different
levels of O2 and this justified strongly the role of HIF-2 on expression
of genes in obesity and inflammation. Hyperplasia and hypertrophy in
adipocytes can lead to many morphological and molecular changes in
adipocytes resulting in hypoxia, metabolic dysregulation and increased
expression and secretion of cytokines (Hosogai et al., 2007, Ye et al.,
2007). Different vital genes involved in metabolic and diet induced
obesity have been reported to be expressed under the action of HIF-1.
Recently, NF-KB has been reported to be induced through hypoxia (Culver et
al., 2010). It has been suggested that the role of HIF-2 and NF-?B can be
considered because of a strong evidence of former (HIF-2) been reported to
be linked with hypoxia inducible inhibition of insulin signaling
(Regazzetti et al., 2009). There is a strong evidence of hypoxia in
obesity (Ye et al., 1997), with a reported finding of HIF-2 to be tissue
specific rather than HIF-1 (Patel et al., 2008).
The potential role of HIF-2 and NF-KB in pathways involving vital
genes and proteins in response of adipocytes to hypoxia needs to be
explored at molecular level to get a better picture and role of hypoxia in
inducing obesity genes expression in this respective report beside
inflammation as per induced.
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Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, and Fujii-Kuriyama Y
(1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-
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Gentil C, Le Jan S, Philippe J, Leibowitch J, Sonigo P, Germain S,
Pi?tri-Rouxel F. Is oxygen a key factor in the lipodystrophy phenotype?
Lipids Health Dis. 2006 Oct 18;5:27.
Hosogai, N., Fukuhara, A., Oshima, K., Miyata, Y., Tanaka, S.,
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Shimomura, I. (2007) Adipose tissue hypoxia in obesity and its impact on
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Llop J, Schlangen K, Fullaondo A, Aransay AM, Mart?n A, Rodr?guez CI.
Prelamin A accumulation and stress conditions induce impaired Oct-1
activity and autophagy in prematurely aged human mesenchymal stem cell.
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Lado-Abeal J, Calvo RM, Victoria B, Castro I, Obregon MJ, Araujo-
Vilar D.Regional decrease of subcutaneous adipose tissue in patients with
type 2 familial partial lipodystrophy is associated with changes in
thyroid hormone metabolism. Thyroid. 2010 Apr;20(4):419-24. doi:
10.1089/thy.2009.0267.
Patel SA, Simon MC. Biology of hypoxia-inducible factor-2alpha in
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Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S.
Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes. 2009
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gene enhancer at a site required for transcriptional activation. Molec.
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Semenza, G. L. (1998). Hypoxia-inducible factor 1: master regulator
of O2 homeostasis. Curr. Opin. Genet. Dev. 8, 588-594.
Wang, G.L., Jiang, B.H., Rue, E.A., Semenza, G.L., 1995.
Hypoxia?inducible factor?1 is a basic? helix?loop?helix?pas heterodimer
regulated by cellular O2 tension. Proc Natl Acad Sci USA 92, 5510?5514.
Wenger, R. H. and Gassmann, M. (1997). Oxygen(es) and the hypoxia-
inducible factor-1. Biol. Chem. 378, 609-616.
Ye, J., Gao, Z., Yin, J., and He, Q. (2007) Hypoxia is a potential
risk factor for chronic inflammation and adiponectin reduction in adipose
tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293,
E1118-1128.
C-terminus truncation of Seipin as a good potential sign of diseases
Wei-Li Yu and Yun Sun
Seipin is a transmembrane protein of the endoplasmic reticulum with N, C-terminus residing the intracytoplasmic side.1 2 Loss of Seipin function has been shown to lead to severe lipodystrophy, motor neuropathy and silver syndrome.3 However, its molecular mechanism is still unknown. Recently Guillén-Navarro E et al 4...
C-terminus truncation of Seipin as a good potential sign of diseases
Wei-Li Yu and Yun Sun
Seipin is a transmembrane protein of the endoplasmic reticulum with N, C-terminus residing the intracytoplasmic side.1 2 Loss of Seipin function has been shown to lead to severe lipodystrophy, motor neuropathy and silver syndrome.3 However, its molecular mechanism is still unknown. Recently Guillén-Navarro E et al 4 indicated that complete skipping of exon 7 was associated with a new neurodegenerative syndrome. The mutation caused early termination, resulting in C-terminally truncated proteins p.Tyr289LeufsX64. It demonstrated that C-terminus of Seipin played a key role in the pathogenesis of this new neurological disease. This result suggests that C-terminus truncation of Seipin might be a good potential prediction of this disease.
Other studies have been carried with the similar aim. Van Maldergem et al 5 had reported that C-terminus deficiency of Seipin due to kipping of exon 7 caused a case of severe psychomotor delay and pyramidal signs. These mutations were associated with intellectual impairment. Furthermore, Yang W et al 6 found that C-terminus truncated proteins such as R275X and Q391X, led to lipodystrophy. It indicated that C-terminus of Seipin could regulate lipogenesis and adipogenesis. In addition, Yang W et al 7 identified that C-terminus of Seipin interacted with 14-3-3β, which patiotemporally recruited an interacting partner of actin-severing protein cofilin-1 during adipocyte differentiation. They proposed that C-terminus of Seipin might regulate adipogenesis by recruiting cofilin-1 to remodel actin cytoskeleton through the 14-3-3β protein.
These findings suggest that C-terminus truncation of Seipin may be a potential sign of diseases such as lipodystrophy, psychomotor delay and neurological diseases. We greatly enjoyed reading the article by Guillén-Navarro E et al and believe C-terminus truncation of Seipin may be useful for prediction of diseases.
The authors declare no conflict of interest.
1. Magré J, Delépine M, Khallouf E, Gedde-Dahl T Jr, Van Maldergem L, Sobel E, Papp J, Meier M, Mégarbané A, Bachy A, Verloes A, d’Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O’Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J; BSCL Working Group. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001; 28: 365-70.
2. Lundin C, Nordstrom R, Wagner K, Windpassinger C, Andersson H, von Heijne G and Nilsson I. Membrane topology of the human seipin protein. FEBS Lett 2006; 580: 2281-2284.
3. Chen W, Yechoor VK, Chang BH, Li MV, March KL, Chan L. The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin plays a key role in adipocyte differentiation. Endocrinology 2009; 150:4552-4561.
4. Encarna Guillén-Navarro, Sofía Sánchez-Iglesias, Rosario Domingo-Jiménez, Berta Victoria, Alejandro Ruiz-Riquelme, Alberto Rábano, Lourdes Loidi, Andrés Beiras, Blanca González-Méndez, Adriana Ramos, Vanesa López-González, María Juliana Ballesta-Martínez, Miguel Garrido-Pumar, Pablo Aguiar, Alvaro Ruibal, Jesús R Requena, and David Araújo-Vilar. A new seipin-associated neurodegenerative syndrome. J Med Genet 2013; 50:401-409.
5. Van Maldergem L, Magré J, Khallouf TE, Gedde-Dahl T Jr, Delépine M, Trygstad O, Seemanova E, Stephenson T, Albott CS, Bonnici F, Panz VR, Medina JL, Bogalho P, Huet F, Savasta S, Verloes A, Robert JJ, Loret H, De Kerdanet M, Tubiana-Rufi N, Mégarbané A, Maassen J, Polak M, Lacombe D, Kahn CR, Silveira EL, D’Abronzo FH, Grigorescu F, Lathrop M, Capeau J, O’Rahilly S. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 2002; 39: 722-33.
6. Yang W, Thein S, Guo X, Xu F, Venkatesh B, Sugii S, Radda GK and Han W. Seipin differentially regulates lipogenesis and adipogenesis through a conserved core sequence and an evolutionarily acquired C-terminus. Biochem J 2013; 452: 37-44.
7. Yang W, Thein S, Wang X, Bi X, Ericksen RE, Xu F, Han W. BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodeling. Human Molecular Genetics 2014; 23: 502-513.
We found this paper to be immensely informative while researching
junctional epidermolysis bullosa (JEB) for a particular clinical case,
which is described below. During the course of testing for this
particular case we found evidence suggesting that that the D982G mutation
in LAMB3 may not be disease-causing.
In their paper, Varki, Sadowski, and Pfender et al. present the case
of an eight-month-old male patie...
We found this paper to be immensely informative while researching
junctional epidermolysis bullosa (JEB) for a particular clinical case,
which is described below. During the course of testing for this
particular case we found evidence suggesting that that the D982G mutation
in LAMB3 may not be disease-causing.
In their paper, Varki, Sadowski, and Pfender et al. present the case
of an eight-month-old male patient who presented with mild blistering of
the legs and feet at birth but who exhibited no further blistering.
Mutation analysis for this boy reportedly revealed two LAMB3 missense
mutations, R366W and D982G. It is not noted if phase of these mutations
is known. The author suggested that the abnormal proteins arising from
these alleles are able to function in the postnatal period, thus leading
to spontaneous amelioration of the phenotype after birth.
Here we present the case of an unaffected parent of a child affected
with Herlitz-JEB (H-JEB) who himself is a compound heterozygote for two
LAMB3 mutations, D982G and 31dupC.
In our case, the second child born to a non-consanguineous Caucasian
couple with no family history of JEB was noted to have open sores soon
after birth. He was diagnosed with H-JEB based on the results of skin
biopsy, and he died at five weeks of age. Molecular genetic testing
identified two LAMB3 premature termination mutations, 31dupC (paternally
inherited) and R635X (maternally inherited). His unaffected father was
also found to carry the D982G mutation.
The 31insC and R635X mutations in LAMB3 have been described in
multiple individuals with H-JEB. To the best of our knowledge, the D982G
missense mutation in LAMB3 has been described only in this paper. Our
finding of this same missense mutation in trans with a more severe LAMB3
mutation in a reportedly completely unaffected individual argues against
D982G being a disease-causing mutation. In addition, this mutation is
predicted to be benign by Polyphen-2.
The findings in our case argue against D982G being a disease-causing
mutation, as had been suggested in this paper. However, the possibility
of reduced penetrance cannot be excluded at this time.
RSS was first described in 1953 [1]. It is a clinically and
genetically heterogeneous condition. Clinical diagnosis is based on
various characteristics including slow growth before and after birth,
relative macrocephaly, a prominent forehead at a young age,
hemihypotrophy, and fifth finger clinodactyly. Five different diagnostic
scoring systems of RSS have been published. These systems take into
account most major clini...
RSS was first described in 1953 [1]. It is a clinically and
genetically heterogeneous condition. Clinical diagnosis is based on
various characteristics including slow growth before and after birth,
relative macrocephaly, a prominent forehead at a young age,
hemihypotrophy, and fifth finger clinodactyly. Five different diagnostic
scoring systems of RSS have been published. These systems take into
account most major clinical features and sometimes minor clinical
features, and are on the whole quite similar. These five scoring systems
were recently compared in the Journal of Medical Genetics in terms of
sensitivity, specificity, and positive or negative predictive value [2].
In this evaluation, the scoring system described by Netchine et al. [3]
showed a high degree of specificity and sensitivity. This scoring system
has also been used by other teams from various countries in the diagnosis
of RSS (see for instance [4]). Furthermore, the article describing this
scoring system [3] was reviewed by the editorial board of The Journal of
Clinical Endocrinology & Metabolism (JCEM) and received an award in
2008 from the Endocrine Society. This article has been cited in PUBMED 128
times.
The first described molecular abnormality in RSS was the maternal
uniparental disomy of chromosome 7 (mUPD7). This defect is present in 5-
10% of individuals affected by RSS [5, 6]. This observation suggests the
aberrant dosage of imprinted genes may be involved in the pathology of
RSS, although the gene(s) involved remain unknown. Recently, abnormalities
of 11p15, a locus also harboring imprinted genes, have been described.
This region contains two separate imprinting clusters: the telomeric
domain (ICR1) that regulates H19 and IGF2, and the centromeric domain
(ICR2) that regulates the long non-coding RNA KCNQ1OT1 and CDKN1C genes.
Of note, cytogenetic, genetic, and epigenetic disturbances of the 11p15
region encompassing ICR1 and ICR2 are associated with the overgrowth
disorder Beckwith Wiedemann syndrome (BWS). BWS is a clinical and
molecular mirror of RSS, and around 8% of cases involve loss of function
mutations of CDKN1C [7]. In RSS, loss of methylation (LOM) of the paternal
ICR1 is the most prevalent defect. This epigenetic change is found in up
to 60% of RSS patients [3, 8], although it has been reported to occur less
frequently in some populations (e.g. with a frequency of ~31% in Japanese
patients) [4]. Approximately 30% of RSS patients are ? idiopathic ? with
no molecular anomaly yet identified.
General comments on the items of the scoring system described in [3]:
Young children with RSS have a very different clinical profile than older
children or adults with RSS. Feeding difficulties are much more pronounced
in early life and therefore have to be assessed at a young age. Older
children and adults may become overweight. Feeding difficulties can be
difficult to assess; therefore, one of the conclusions of our paper in
2007 was to replace the item ? feeding difficulties ? with ? feeding
difficulties and /or a BMI two SDs below the mean at around two years of
age ?. The prominent forehead is distinct from relative macrocephaly.
Indeed, relative macrocephaly is characterized by a growth restriction
affecting mostly the body, whereas circumference of the head is relatively
less unaffected. A prominent forehead however, is a dysmorphic feature
that describes the characteristic shape of these patients' forehead
protruding over the plane of the face. This feature tends to disappear in
late childhood and therefore has to be assessed around two years of age.
Body asymmetry is a feature of RSS, but is not present in all RSS
patients. This feature is more frequent in RSS patients with epigenetic
changes to 11p15 than in patients with mUPD7. For example, in our sample
of 145 RSS patients with 11p15 LOM, 79% of patients had hemihypotrophy,
whereas in a sample of 16 RSS patients with mUPD7, none of the patients
were affected by hemihypotrophy (p<0.0001). This is probably due to the
fact that the 11p15 LOM occurs in a mosaic manner, such that the
proportion of cells that possess this epigenetic change may differ between
the left and right side of the body. The item post natal growth
retardation also has to be assessed around two years of age. This is
because most RSS patients are treated with growth hormone generally
starting between two and four years of age, to improve their growth rate.
Bone age and pubertal status also has to be taken into account when
analyzing the growth of a child affected by RSS. Indeed, these children
frequently have an advanced bone age due to aggressive adrenarche and
early puberty. Thus, even though their height may be normal during
childhood, their final height may be lower than average due to premature
bone fusion.
Specific comments in response to this letter
The diagnosis of RSS in the patients reported by Brioude et al. is not
questionable because all the patients carrying the mutation fulfilled the
clinical criteria of RSS as described by Netchine et al. in 2007.
Furthermore, these patients also fulfill the RSS clinical criteria
according to other validated RSS clinical scoring systems such as the
Birmingham scoring system [2]. However, as mentioned above, the clinical
diagnosis of RSS is often difficult. RSS scoring systems are helpful to
orient the diagnosis; nonetheless, it is also very important that an
experienced clinical geneticist or pediatrician make this diagnosis. The
pediatrician (IO) who referred this family to our laboratory has a lot of
clinical experience in RSS and has followed two generations of this family
(second and third). The pediatrician (IO) became convinced of the
diagnosis of a very rare case of familial RSS when the third generation of
this family came to the clinic for consultation.
In the clinical scoring system described by Netchine et al. [3], body
asymmetry is one of the six criteria for the clinical diagnosis of RSS.
However, in a family carrying a CDKN1C mutation, body asymmetry is not
expected to occur because the molecular defect is present in all the cells
of the body (unlike the mosaic epigenetic change at the 11p15 locus). This
hypothesis is in accordance with the observation that patients with
Beckwith Wiedemann syndrome who carry CDKN1C loss of function mutations
are not usually affected by body asymmetry [7]. Similarly, patients with
IMAGe syndrome with a mutation in CDKN1C do not have body asymmetry [9].
Thus, the absence of body asymmetry does not exclude the diagnosis of RSS
in this particular case. Furthermore, we found that RSS patients with
mUPD7 do not show body asymmetry, and some RSS patients with 11p15 LOM are
also unaffected (20% in our sample of patients).
As mentioned above, all the patients described here had feeding
difficulties and/or a BMI two SDs below the mean at around two years of
age. We can consider a low BMI to be equivalent to feeding difficulties,
as mentioned in the legend of table 2 and proposed in our paper in 2007
[3].
Relative macrocephaly was not present at birth for all the patients
presented here (notably in the propositus IV.1). However, this trait was
present at two years of age in all patients carrying the mutation.
Therefore, this characteristic may help to distinguish RSS patients with a
mutation in CDKN1C from patients with 11p15 LOM. However, the absence of
relative macrocephaly is not enough to preclude the clinical diagnosis of
RSS in these patients. Although the triangular face does not appear to be
obvious in the pictures of the patients, this feature has been confirmed
by the patients' physician (IO). Furthermore, this trait (triangular face
and prominent forehead) is usually less obvious in adult patients.
Besides, a triangular face is not a clinical criterion for RSS diagnosis
and is not part of our scoring system.
All the patients described here presented growth retardation: Length at
birth and then height and/or weight was two SDs below the mean according
to French reference charts both at birth and after birth. All the
patients with the CDKN1C mutation did not attain a normal height at the
age of 2 years. Patient III.7 received a long-term therapy consisting of
growth hormones and Triptorelin acetate and thus reached a final height of
157 cm. However this patient's sister, (patient III.6) received growth
hormone therapy for a shorter duration than her sister resulting in a
lower final height. Today, most RSS patients are treated with growth
hormones and the best improvement in final height is attained when the
rapid advancement in bone age is also treated.
Individuals II.4 and III.10 do not carry the CDKN1C mutation, and cannot
be considered as having RSS because they do not present the clinical
criteria as described above. These two individuals did not show relative
macrocephaly at birth or at the age of two years. Their size at birth was
either normal (II.4), or, in the case of III.10, small, but nonetheless
larger than new-born babies corresponding to family members who carry the
mutations. Individuals II.4 and III.10 had a normal BMI, and II.4 had a
normal adult height without any therapy. We agree with the point that
individual III.10 showed a short final height despite growth hormone
therapy. This patient was followed like the other patients with short
stature of this family by the same pediatrician (IO), who did not
clinically assess her as having RSS. To date, the causal mechanism of her
short adult height has not been elucidated.
CONCLUSION
Defining the clinical criteria of a clinically and molecularly
heterogeneous syndrome like RSS is not straightforward. Nonetheless, we
are convinced that the family described here, represents a rare case of
familial RSS. The diagnosis of RSS was made by a physician experienced in
RSS who had the opportunity to follow and treat two generations of this
exceptional family. The scoring system described by Netchine et al. [3],
but also other RSS scoring systems such as those evaluated by Dias et al.
[2] also favor this diagnosis. The absence of body asymmetry does not
rule out the diagnosis of RSS, as in mUPD7 RSS cases or in 20% of 11p15
LOM cases. In this case, the absence of body asymmetry is consistent
with the genetic cause identified. This CDKN1C mutation is therefore a new
genetic cause of familial RSS.
The CDKN1C mutation identified in this RSS familial case affects the same
amino acid as a mutation described by Arboleda et al. [9] in patients
with IMAGe syndrome. This observation will be of great interest for the
readers of The Journal of Medical Genetics. IMAGe syndrome has some
similarities with RSS, including fetal and postnatal growth retardation
and a prominent forehead, but is also typically characterized by bone
anomalies and a severe adrenal insufficiency that were not present in
this family. It is striking to note that a mutation on the exact same
amino acid, but with a different substitution, can lead to severe adrenal
insufficiency in one case and a normal adrenal function in the other case,
and therefore to two distinct syndromes.
As of 2013, 60 years after the first description of RSS, several molecular
causes of RSS have been identified (mUPD7 and various types of 11p15
anomalies) accounting for about 70% of etiologies. We suggest that CDKN1C
mutations are a new molecular cause of familial RSS. Given the clinical
and molecular heterogeneity of RSS we suggest that RSS should no longer be
considered as a syndrome but as a spectrum of disorders with a variety of
causes. This would make it easier to understand why RSS is clinically and
molecularly heterogeneous. However, it is important for RSS patients to be
identified as belonging to a same spectrum and not to multiple categories
of very rare conditions, because these patients share a lot of clinical
manifestations and have similar treatment needs. This will allow the
development of common clinical guidelines for these patients, and well
help in the implementation of clinical trials that are always difficult
to establish for rare diseases. The identification of exact genetic defect
is also a cornerstone for an accurate genetic counseling.
1 Silver HK, Kiyasu W, George J, Deamer WC. Syndrome of congenital
hemihypertrophy, shortness of stature, and elevated urinary gonadotropins.
Pediatrics 1953;12(4):368-76.
2 Dias RP, Nightingale P, Hardy C, Kirby G, Tee L, Price S, Macdonald F,
Barrett TG, Maher ER. Comparison of the clinical scoring systems in Silver
-Russell syndrome and development of modified diagnostic criteria to guide
molecular genetic testing. J Med Genet 2013;50(9):635-9.
3 Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, Houang
M, Steunou V, Esteva B, Thibaud N, Demay MC, Danton F, Petriczko E,
Bertrand AM, Heinrichs C, Carel JC, Loeuille GA, Pinto G, Jacquemont ML,
Gicquel C, Cabrol S, Le Bouc Y. 11p15 imprinting center region 1 loss of
methylation is a common and specific cause of typical Russell-Silver
syndrome: clinical scoring system and epigenetic-phenotypic correlations.
J Clin Endocrinol Metab 2007;92(8):3148-54.
4 Fuke T, Mizuno S, Nagai T, Hasegawa T, Horikawa R, Miyoshi Y, Muroya K,
Kondoh T, Numakura C, Sato S, Nakabayashi K, Tayama C, Hata K, Sano S,
Matsubara K, Kagami M, Yamazawa K, Ogata T. Molecular and clinical studies
in 138 Japanese patients with Silver-Russell syndrome. PLoS One
2013;8(3):e60105.
5 Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H,
Mehes K, Hamel BC, Otten BJ, Hergersberg M, et al. Uniparental disomy 7 in
Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet
1995;4(4):583-7.
6 Preece MA, Price SM, Davies V, Clough L, Stanier P, Trembath RC, Moore
GE. Maternal uniparental disomy 7 in Silver-Russell syndrome. J Med Genet
1997;34(1):6-9.
7 Brioude F, Lacoste A, Netchine I, Vazquez MP, Auber F, Audry G, Gauthier
-Villars M, Brugieres L, Gicquel C, Le Bouc Y, Rossignol S. Beckwith-
Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular
Mechanism, and Guidelines for Tumor Surveillance. Horm Res Paediatr
2013;80:457-65.
8 Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton
F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y.
Epimutation of the telomeric imprinting center region on chromosome 11p15
in Silver-Russell syndrome. Nat Genet 2005;37(9):1003-7.
9 Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B,
Delot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergada I, Dell'angelica
EC, Nelson SF, Martinez-Agosto JA, Achermann JC, Vilain E. Mutations in
the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet
2012;44(7):788-92.
Response to e letter ID jmedgenet el; 2826 by Refaeli et al., dated June14, 2016 A considerable amount of literature on the role of podocalyxin-like (PODXL) protein in normal mammalian kidney functions and to a lesser extent in mouse brain development is available. We agree that these studies particularly, "Anuria, Omphalocele, and Perinatal Lethality in Mice Lacking the Cd34-Related Protein Podocalyxin" by Doyonnas et...
Re:
Sudhaman, et al. Discovery of a frameshift mutation in podocalyxin- like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med Genet. 0:1-7, 2016.
In the February 2016 edition of the Journal of Medical Genetics, Sudhaman et al(1) report the identification of a PODXL variant (c.89_90insGTCGCCCC) as the causative mutation in an Indian fam...
I just read the articles on SMA1, SMA2, SMA3. I felt it important to tell you of my son, born 1/26/70. When I took him to his first checkup at 3 months old, I voiced my concern for his floppy head. Again at 6 months old, when he couldn't sit up, roll over, kick against resistance. Finally, the Pediatrician agreed to get an appointment with Yale Hospital in CT at 8 mos. The biopsy was shown to be SMA 1. We weren't given...
I wish to thank the authors of the review (1) of my book on scientific writing (2). Here are further free documents for authors: the Micro-Article, described in the book, is a template allowing to identify the main discovery before starting to write an article (3). Writing a Review Article in 7 Steps is a short note providing guidelines to write a review or a book chapter (4). This note proposes in particular a convenie...
I wish to thank the authors of the review (1) of my book on scientific writing (2). Here are further free documents for authors: the Micro-Article, described in the book, is a template allowing to identify the main discovery before starting to write an article (3). Writing a Review Article in 7 Steps is a short note providing guidelines to write a review or a book chapter (4). This note proposes in particular a convenie...
Letter to Editor Shaheen et al. 1 recently reported a homozygous 5 bps deletion mutation (c.1299_1303delTAAG; p.Phe433Leufs*6) in the human polo-like kinase 4 (PLK4,MIM 605031) gene and proposed that it is a compelling candidate for primordial dwarfism (PD). Autozygosity mapping and LOD score, method of estimating linkage distances, are adopted for the novel locus identification. Candidate gene hunting among 144 in the r...
I have read all the respective article and I agreed to most of the findings. Recently, our group has been working with metabolomics towards lipodystropy and we did found similar findings. Recently it has been reported (Abael et al., 2010) that the changes in local thyroid hormone (TH) metabolism may occur in areas with lipoatrophy. These changes could be because of different molecular mechanisms (for example; levels of...
C-terminus truncation of Seipin as a good potential sign of diseases
Wei-Li Yu and Yun Sun
Seipin is a transmembrane protein of the endoplasmic reticulum with N, C-terminus residing the intracytoplasmic side.1 2 Loss of Seipin function has been shown to lead to severe lipodystrophy, motor neuropathy and silver syndrome.3 However, its molecular mechanism is still unknown. Recently Guillén-Navarro E et al 4...
We found this paper to be immensely informative while researching junctional epidermolysis bullosa (JEB) for a particular clinical case, which is described below. During the course of testing for this particular case we found evidence suggesting that that the D982G mutation in LAMB3 may not be disease-causing.
In their paper, Varki, Sadowski, and Pfender et al. present the case of an eight-month-old male patie...
RSS was first described in 1953 [1]. It is a clinically and genetically heterogeneous condition. Clinical diagnosis is based on various characteristics including slow growth before and after birth, relative macrocephaly, a prominent forehead at a young age, hemihypotrophy, and fifth finger clinodactyly. Five different diagnostic scoring systems of RSS have been published. These systems take into account most major clini...
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