Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia

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 hyperkeratosi...

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Bibliographic Details
Published in:Journal of investigative dermatology 2017-11, Vol.137 (11), p.2344-2353
Main Authors: Takeichi, Takuya, Torrelo, Antonio, Lee, John Y.W., Ohno, Yusuke, Lozano, María Luisa, Kihara, Akio, Liu, Lu, Yasuda, Yuka, Ishikawa, Junko, Murase, Takatoshi, Rodrigo, Ana Belén, Fernández-Crehuet, Pablo, Toi, Yoichiro, Mellerio, Jemima, Rivera, José, Vicente, Vicente, Kelsell, David P., Nishimura, Yutaka, Okuno, Yusuke, Kojima, Daiei, Ogawa, Yasushi, Sugiura, Kazumitsu, Simpson, Michael A., McLean, W.H. Irwin, Akiyama, Masashi, McGrath, John A.
Format: Article
Language:English
Subjects:
Adolescent
Alcohol Oxidoreductases - genetics
Alleles
Biopsy, Needle
Ceramides - biosynthesis
Child
Genetic Predisposition to Disease
Humans
Immunohistochemistry
In Vitro Techniques
Keratoderma, Palmoplantar - complications
Keratoderma, Palmoplantar - genetics
Keratoderma, Palmoplantar - pathology
Male
Mutation
Pedigree
Prognosis
Sampling Studies
Severity of Illness Index
Thrombocytopenia - complications
Thrombocytopenia - diagnosis
Young Adult
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Summary: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, soles, and anogenital skin, whereas the other two had more severe, generalized harlequin ichthyosis-like skin. Thrombocytopenia was present in all patients. The mutations in KDSR were associated with reduced ceramide levels in skin and impaired platelet function. KDSR enzymatic activity was variably reduced in all patients, resulting in defective acylceramide synthesis. Mutations in KDSR have recently been reported in inherited recessive forms of progressive symmetric erythrokeratoderma, but our study shows 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.
ISSN:0022-202X
1523-1747
DOI:10.1016/j.jid.2017.06.028