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 Mellerio, José Rivera, Vicente Vicente, David P. Kelsell, Yutaka Nishimura, Yusuke Okuno, Daiei Kojima & 6 others Yasushi Ogawa, Kazumitsu Sugiura, Michael A. Simpson, W. H.Irwin McLean, Masashi Akiyama, John A. McGrath

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2344-2353
Number of pages10
JournalJournal of Investigative Dermatology
Volume137
Issue number11
DOIs
Publication statusPublished - 01-11-2017

Fingerprint

Ceramides
Thrombocytopenia
Skin
Mutation
Biosynthesis
Platelets
Blood Platelets
Lamellar Ichthyosis
Exome
Ichthyosis
Biological Phenomena
Sphingosine
Tissue
Phenotype
Enzymes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

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. / Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. In: Journal of Investigative Dermatology. 2017 ; Vol. 137, No. 11. pp. 2344-2353.
@article{07c39a9c8146480ea010cb7407d060dd,
title = "Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia",
abstract = "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.",
author = "Takuya Takeichi and Antonio Torrelo and Lee, {John Y.W.} and Yusuke Ohno and Lozano, {Mar{\'i}a Luisa} and Akio Kihara and Lu Liu and Yuka Yasuda and Junko Ishikawa and Takatoshi Murase and Rodrigo, {Ana Bel{\'e}n} and Pablo Fern{\'a}ndez-Crehuet and Yoichiro Toi and Jemima Mellerio and Jos{\'e} Rivera and Vicente Vicente and Kelsell, {David P.} and Yutaka Nishimura and Yusuke Okuno and Daiei Kojima and Yasushi Ogawa and Kazumitsu Sugiura and Simpson, {Michael A.} and McLean, {W. H.Irwin} and Masashi Akiyama and McGrath, {John A.}",
year = "2017",
month = "11",
day = "1",
doi = "10.1016/j.jid.2017.06.028",
language = "English",
volume = "137",
pages = "2344--2353",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "11",

}

Takeichi, T, Torrelo, A, Lee, JYW, Ohno, Y, Lozano, ML, Kihara, A, Liu, L, Yasuda, Y, Ishikawa, J, Murase, T, Rodrigo, AB, Fernández-Crehuet, P, Toi, Y, Mellerio, J, Rivera, J, Vicente, V, Kelsell, DP, Nishimura, Y, Okuno, Y, Kojima, D, Ogawa, Y, Sugiura, K, Simpson, MA, McLean, WHI, Akiyama, M & McGrath, JA 2017, 'Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia', Journal of Investigative Dermatology, vol. 137, no. 11, pp. 2344-2353. https://doi.org/10.1016/j.jid.2017.06.028

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

In: Journal of Investigative Dermatology, Vol. 137, No. 11, 01.11.2017, p. 2344-2353.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia

AU - Takeichi, Takuya

AU - Torrelo, Antonio

AU - Lee, John Y.W.

AU - Ohno, Yusuke

AU - Lozano, María Luisa

AU - Kihara, Akio

AU - Liu, Lu

AU - Yasuda, Yuka

AU - Ishikawa, Junko

AU - Murase, Takatoshi

AU - Rodrigo, Ana Belén

AU - Fernández-Crehuet, Pablo

AU - Toi, Yoichiro

AU - Mellerio, Jemima

AU - Rivera, José

AU - Vicente, Vicente

AU - Kelsell, David P.

AU - Nishimura, Yutaka

AU - Okuno, Yusuke

AU - Kojima, Daiei

AU - Ogawa, Yasushi

AU - Sugiura, Kazumitsu

AU - Simpson, Michael A.

AU - McLean, W. H.Irwin

AU - Akiyama, Masashi

AU - McGrath, John A.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85032028583&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032028583&partnerID=8YFLogxK

U2 - 10.1016/j.jid.2017.06.028

DO - 10.1016/j.jid.2017.06.028

M3 - Article

VL - 137

SP - 2344

EP - 2353

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 11

ER -