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• SDR9C7, KRT83, and increasing verisimilitude
  Richard A. Spritz, Khadim Shah
  Published on: 25 September 2020
• KRT83 mutations are not associated with progressive symmetric erythrokeratoderma
  Judith Fischer
  Published on: 17 September 2020
• Could a mutation in the hair keratin KRT83 cause recessive progressive symmetric erythrokeratoderma?
  Yuval Ramot
  Published on: 18 February 2017

• Published on: 25 September 2020

  SDR9C7, KRT83, and increasing verisimilitude

  • Richard A. Spritz, Professor and Director Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO USA
  • Other Contributors:
    • Khadim Shah, Assistant Professor

  Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.

  We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.

  Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.

  With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consisten...

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  Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.

  We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.

  Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.

  With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consistent with the diagnosis of congenital ichthyosis, resulting from the homozygous frameshift of SDR9C7. That places the true role of the KRT83 frameshift in this family into question. It is noteworthy that affected members of this family exhibit the additional clinical feature of striking erythrokeratoderma, not evident in affected members of the Pakistani family reported by Karim et al. [4] who carry the same SDR9C7 frameshift but not the frameshift in KRT83. Whether prominent erythrokeratoderma might be an atypical feature of congenital ichthyosis in this family, an epistatic effect of an unknown common unlinked variant in this population, whether that might reflect a specific effect of the additional homozygous KRT83 frameshift, or whether that might be a summary effect of the SDR9C7 and KRT83 frameshifts in perfect linkage disequilibrium in this family remains to be determined. Increasing verisimilitude indeed!

  1. Niiniluoto I. Verisimilitude: the third period. Br J Phil Sci 1998;49:1–29.
  2. Shah K, Ansar M, Mughal Z, Khan F, Ahmad W, Ferrara T, Spritz R. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet 2017;54:186-9.
  3. Shigehara Y, Okuda S, Nemer G, Chedraoui A, Hayashi R, Bitar F, Nakai H, Abbas O, Daou L, Abe R, Sleiman MB, Kibbi AG, Kurban M, Shimomura Y. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet 2016;25:4484–93.
  4. Karim N, Murtaza G, Naeem M. Whole‐exome sequencing identified a novel frameshift mutation in SDR9C7 underlying autosomal recessive congenital ichthyosis in a Pakistani family. Br J Dermatol 2017; 177: e191–2.
  5. Takeichi T, Nomura T, Takama H, Kono M, Sugiura K, Watanabe D, Shimizu H, Simpson MA, McGrath JA, Akiyama M. Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7. Br J Dermatol 2017;177: e62–4.
  6. Hotz A, Fagerberg C, Vahlquist A, Bygum A, Törmä H, Rauschendorf MA, Zhang H, Heinz L, Bourrat E, Hausser I, Vestergaard V, Dragomir A, Zimmer AD, Fischer J. Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis. Br J Dermatol 2018;178:e207-e209.

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  Conflict of Interest:
  None declared.

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• Published on: 17 September 2020

  KRT83 mutations are not associated with progressive symmetric erythrokeratoderma

  • Judith Fischer, Chair, Medical director, Specialist for genodermatoses Institute of Human Genetics, University Medical Center Freiburg, Freiburg, Germany

  I recently came across this publication and was very surprised at some facts that seem inconsistent.
  Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
  First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
  In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
  To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...

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  I recently came across this publication and was very surprised at some facts that seem inconsistent.
  Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
  First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
  In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
  To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but also a homozygous frameshift mutation in the gene SDR9C7 (p.Thr122Asnfs).
  The first publication that mutations in the SDR9C7 gene lead to autosomal recessive congenital ichthyosis (ARCI) was published in 2017 (2), followed by several others (3,4). Karim et al. then described the same frame shift mutation as Shah et al. (p.Thr122Asnfs) in SDR9C7 in Pakistani patients with autosomal recessive congenital ichthyosis (5).
  May be it would be appropriate to write an erratum, or to correct the article under these new aspects.

  1. Shah K, Ansar M, Mughal ZU et al. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet. 2017 Mar;54(3):186-189
  2. Shigehara Y, Okuda S, Nemer G et al . Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet 2016; 25: 4484– 93.
  3. Takeichi T, Nomura T, Takama H et al . Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7 . Br J Dermatol 2017; 177: e62– 4.
  4. Hotz A, Fagerberg C, Vahlquist A, Bygum A, Törmä H, Rauschendorf MA, Zhang H, Heinz L, Bourrat E, Hausser I, Vestergaard V, Dragomir A, Zimmer AD, Fischer J. Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis. Br J Dermatol. 2018 Mar;178(3):e207-e209.
  5. Karim N, Murtaza G, Naeem M. Whole‐exome sequencing identified a novel frameshift mutation in SDR9C7 underlying autosomal recessive congenital ichthyosis in a Pakistani family. Br J Dermatol 2017; 177: e191– 2.

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  Conflict of Interest:
  None declared.

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• Published on: 18 February 2017

  Could a mutation in the hair keratin KRT83 cause recessive progressive symmetric erythrokeratoderma?

  • Yuval Ramot, Senior physician
  • Other Contributors:
    • Abraham Zlotogorski and Maurice van Steensel

  Yuval Ramot1, Abraham Zlotogorski1, Maurice van Steensel2,3,4

  1 Department of Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel

  2 School of Medicine and School of Life Sciences, University of Dundee, United Kingdom

  3 Institute of Medical Biology, Singapore

  4 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

  In their rec...

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  Yuval Ramot1, Abraham Zlotogorski1, Maurice van Steensel2,3,4

  1 Department of Dermatology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel

  2 School of Medicine and School of Life Sciences, University of Dundee, United Kingdom

  3 Institute of Medical Biology, Singapore

  4 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

  In their recently published article, Shah et al. claim that a homozygous loss-of-function mutation in KRT83 leads to recessive progressive symmetric erythrokeratoderma.1 However, since KRT83 encodes a hair-specific keratin, we believe it is highly unlikely that a mutation in this gene would cause a strictly epidermal phenotype.

  Keratins are intermediate filaments that provide structural support to epithelial cells, in addition to other biological properties.2-4 They are unique in that each has a very specific expression pattern, which has been studied extensively.5 To date, mutations in hair keratins have all been associated with phenotypes restricted to the hairs and nails.6 Specifically, mutations in KRT83 had been linked exclusively to monilethrix.7,8

  Progressive symmetric erythrokeratoderma and erythrokeratoderma variabilis do not present with a hair phenotype. These strictly epidermal disorders are presently grouped together as erythrokeratodermia variabilis et progressiva (OMIM #133200) because they have the same molecular basis - mostly autosomal dominant mutations in GJB3 and GJB4.9 The encoded proteins are highly expressed in the epidermis.9,10

  In their discussion, the authors state that keratin K83 is also expressed outside of the hair follicle. They claim that Kb23, which is the rat ortholog for K83, is expressed in the whole skin, but the reference that they cite has only demonstrated expression in the hair follicle, and not the epidermis.11 The same is true for the claimed expression in the sheep wool follicles, where the reference cited shows expression only in the wool follicle, and not the epidermis.12 Shah et al. also claim that according to the human protein atlas, K83 is expressed in the skin, but actually, it was found only in the hair and not in the epidermis (http://www.proteinatlas.org/ENSG00000170523-KRT83/tissue). Staining as shown in the atlas is highly restricted, even though the antibody used in the human protein atlas is likely to recognize additional hair keratins. The expression atlas that is also cited in the article gives information on expression patterns of genes (http://www.ebi.ac.uk/gxa/home), and is not based on immunohistochemistry as stated by the authors. Since the skin samples used for expression profiling in this database are of whole skin and not the epidermis alone, they are likely to also include parts of hair follicles. Obviously, expression of KRT83 could be observed in these samples. In contrast, a large number of studies demonstrate robust, specific and reproducible expression of K83 in the hair.5,13-15 Thus, we feel that it is safe to conclude that K83 is hair-specific and is not expressed in human epidermis.

  We consider it unlikely that mutations in a keratin that is exclusively expressed in the hair would cause a severe epidermal phenotype that also involves the palms and soles, areas that are devoid of hair follicles. If they did, there would be profound implications for our understanding of keratins, and of skin biology in general. We believe that such a provocative claim should have been accompanied by proper demonstration that K83 is indeed expressed in the epidermis, and functional evidence that its loss can lead to an epidermal-specific phenotype.

  References

  1 Shah K, Ansar M, Mughal ZU et al. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet 2016, Dec 13, Epub ahead of print.

  2 Ramot Y, Zlotogorski A. Keratins: the hair shaft's backbone revealed. Exp Dermatol 2015; 24: 416-7.

  3 Ramot Y, Paus R. Harnessing neuroendocrine controls of keratin expression: a new therapeutic strategy for skin diseases? Bioessays 2014; 36: 672-86.

  4 Ramot Y, Paus R, Tiede S et al. Endocrine controls of keratin expression. Bioessays 2009; 31: 389-99.

  5 Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol 2008; 129: 705-33.

  6 Ramot Y, Zlotogorski A. Molecular genetics of alopecias. Curr Probl Dermatol 2015; 47: 87-96.

  7 van Steensel M, Vreeburg M, Urbina MT et al. Novel KRT83 and KRT86 mutations associated with monilethrix. Exp Dermatol 2015; 24: 222-4.

  8 van Steensel MA, Steijlen PM, Bladergroen RS et al. A missense mutation in the type II hair keratin hHb3 is associated with monilethrix. J Med Genet 2005; 42: e19.

  9 van Steensel MA, Oranje AP, van der Schroeff JG et al. The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. Am J Med Genet A 2009; 149A: 657-61.

  10 Ishida-Yamamoto A, McGrath JA, Lam H et al. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope. Am J Hum Genet 1997; 61: 581-9.

  11 Nanashima N, Akita M, Yamada T et al. The hairless phenotype of the Hirosaki hairless rat is due to the deletion of an 80-kb genomic DNA containing five basic keratin genes. J Biol Chem 2008; 283: 16868-75.

  12 Yu Z, Wildermoth JE, Wallace OA et al. Annotation of sheep keratin intermediate filament genes and their patterns of expression. Exp Dermatol 2011; 20: 582-8.

  13 Langbein L, Yoshida H, Praetzel-Wunder S et al. The keratins of the human beard hair medulla: the riddle in the middle. J Invest Dermatol 2010; 130: 55-73.

  14 Langbein L, Schweizer J. Keratins of the human hair follicle. Int Rev Cytol 2005; 243: 1-78.

  15 Langbein L, Rogers MA, Winter H et al. The catalog of human hair keratins. II. Expression of the six type II members in the hair follicle and the combined catalog of human type I and II keratins. J Biol Chem 2001; 276: 35123-32.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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