Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

Lynn M. Boyden, Nicholas G. Vincent, Jing Zhou, Ronghua Hu, Brittany G. Craiglow, Susan J. Bayliss, Ilana S. Rosman, Anne W. Lucky, Luis A. Diaz, Lowell A. Goldsmith, Amy S. Paller, Richard P. Lifton, Susan J. Baserga, Keith A. Choate*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)978-984
Number of pages7
JournalAmerican journal of human genetics
Issue number6
StatePublished - Jun 1 2017


  • KDSR
  • TSC10
  • ceramide
  • erythrokeratoderma
  • genome sequencing
  • ichthyosis
  • inversion
  • isotretinoin
  • skin
  • splicing

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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