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Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix
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  • Published on:
    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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    Conflict of Interest:
    None declared.
  • Published on:
    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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    Conflict of Interest:
    None declared.
  • Published on:
    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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    Conflict of Interest:
    None declared.