Biallelic mutations in KDSR disrupt ceramide synthesis and result in a spectrum of keratinization disorders associated with thrombocytopenia

Takuya Takeichi, Antonio Torrelo, John Y. W. Lee, Yusuke Ohno, María Luisa Lozano, Akio Kihara, Lu Liu, Yuka Yasuda, Junko Ishikawa, Takatoshi Murase, Ana Belén Rodrigo, Pablo Fernández-Crehuet, Yoichiro Toi, Jemima E. Mellerio, José Rivera, Vicente Vicente, David P. Kelsell, Yutaka Nishimura, Yusuke Okuno, Daiei KojimaYasushi Ogawa, Kazumitsu Sugiura, Michael A. Simpson, W. H. Irwin McLean, Masashi Akiyama, John A. McGrath (Lead / Corresponding author)

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Mutations in ceramide biosynthesis pathways have been implicated in a few Mendelian disorders of keratinization although ceramides are known to have key roles in several biological processes in skin and other tissues. Using whole-exome sequencing in four probands with undiagnosed skin hyperkeratosis/ichthyosis, we identified compound heterozygosity for mutations in KDSR, encoding an enzyme in the de novo synthesis pathway of ceramides. Two individuals had hyperkeratosis confined to palms and soles as well as anogenital skin, whereas the other two had more severe, generalized harlequin ichthyosis-like skin. Of note, thrombocytopenia was present in all cases. The mutations in KDSR were associated with reduced ceramide levels in skin and impaired platelet function. KDSR enzymatic activity was variably reduced in all cases resulting in defective acylceramide synthesis. Mutations in KDSR have recently been reported in inherited recessive forms of progressive symmetric erythrokeratoderma, but our study demonstrates that biallelic mutations in KDSR are implicated in an extended spectrum of disorders of keratinization in which thrombocytopenia is also part of the phenotype. Mutations in KDSR cause defective ceramide biosynthesis, underscoring the importance of ceramide and sphingosine synthesis pathways in skin and platelet biology.

Original languageEnglish
Pages (from-to)2344-2353
Number of pages10
JournalJournal of Investigative Dermatology
Issue number11
Early online date31 Jul 2017
Publication statusPublished - Nov 2017


  • Keratoderma
  • Ichthyosis
  • Thrombocytopenia
  • KDSR
  • Ceramide


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