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.
References:
Culver C, Sundqvist A, Mudie S, Melvin A, Xirodimas D, Rocha S.
Mechanism of hypoxia-induced NF-kappaB. Mol Cell Biol. 2010
Oct;30(20):4901-21. doi: 10.1128/MCB.00409-10.
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-
inducible factor 1alpha regulates the VEGF expression and is potentially
involved in lung and vascular development. Proc Natl Acad Sci USA 94: 4273
-4278.
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.,
Segawa, K., Furukawa, S., Tochino, Y., Komuro, R., Matsuda, M., and
Shimomura, I. (2007) Adipose tissue hypoxia in obesity and its impact on
adipocytokine dysregulation. Diabetes 56, 901-911.
Infante A, Gago A, de Eguino GR, Calvo-Fern?ndez T, G?mez-Vallejo V,
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.
Aging (Albany NY). 2014 Apr;6(4):264-80.
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
development and disease. Cell Death Differ. 2008 Apr;15(4):628-34. doi:
10.1038/cdd.2008.17. Epub 2008 Feb 15. Review. PubMed PMID: 18259197;
PubMed Central PMCID:PMC2882207.
Regazzetti C, Peraldi P, Gr?meaux T, Najem-Lendom R, Ben-Sahra I,
Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S.
Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes. 2009
Jan;58(1):95-103. doi: 10.2337/db08-0457.
Tian H, McKnight SL, and Russell DW (1997) Endothelial PAS domain
protein 1 (EPAS1), a transcription factor selectively expressed in
endothelial cells. Genes Dev 11: 72-82.
Semenza, G. L. and Wang, G. L. (1992). A nuclear factor induced by
hypoxia via de novo protein synthesis binds to the human erythropoietin
gene enhancer at a site required for transcriptional activation. Molec.
cell. Biol. 12, 5447-5454.
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.
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 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
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...
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 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...
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