Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.

TitleMutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.
Publication TypeJournal Article
Year of Publication2017
AuthorsBoyden, LM, Vincent, NG, Zhou, J, Hu, R, Craiglow, BG, Bayliss, SJ, Rosman, IS, Lucky, AW, Diaz, LA, Goldsmith, LA, Paller, AS, Lifton, RP, Baserga, SJ, Choate, KA
JournalAm J Hum Genet
Date Published2017 Jun 01
KeywordsAlcohol Oxidoreductases, Ceramides, Genes, Recessive, Genetic Complementation Test, Genetic Predisposition to Disease, Heterozygote, Humans, Intermediate Filament Proteins, Keratosis, Mutation, Polymorphism, Single Nucleotide, RNA Splicing, Saccharomyces cerevisiae

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

Alternate JournalAm. J. Hum. Genet.
PubMed ID28575652
PubMed Central IDPMC5473720
Grant ListT32 GM007223 / GM / NIGMS NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 AR032599 / AR / NIAMS NIH HHS / United States
R01 AR068392 / AR / NIAMS NIH HHS / United States
R01 GM115710 / GM / NIGMS NIH HHS / United States