2. Academic Validation
  3. Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

  • Am J Hum Genet. 2017 Jun 1;100(6):978-984. doi: 10.1016/j.ajhg.2017.05.003.
Lynn M Boyden 1,  Nicholas G Vincent 2,  Jing Zhou 3,  Ronghua Hu 3,  Brittany G Craiglow 3,  Susan J Bayliss 4,  Ilana S Rosman 4,  Anne W Lucky 5,  Luis A Diaz 6,  Lowell A Goldsmith 6,  Amy S Paller 7,  Richard P Lifton 1,  Susan J Baserga 8,  Keith A Choate 9
Affiliations

Affiliations

  • 1 Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 2 Department of Microbiology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 3 Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 4 Division of Dermatology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 5 Dermatologists of Southwest Ohio, Cincinnatti, OH 45247, USA.
  • 6 Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC 27516, USA.
  • 7 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 8 Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 9 Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: [email protected].
PMID: 28575652 DOI: 10.1016/j.ajhg.2017.05.003
Abstract

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.

Keywords

KDSR; TSC10; ceramide; erythrokeratoderma; genome sequencing; ichthyosis; inversion; isotretinoin; skin; splicing.

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