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Title: Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome
Authors: Sérgio B. Sousa
Dagan Jenkins
Estelle Chanudet
Guergana Tasseva
Miho Ishida
Glenn Anderson
James Docker
Mina Ryten
Joaquim Sa
Jorge M. Saraiva
Angela Barnicoat
Richard Scott
Alistair Calder
Duangrurdee Wattanasirichaigoon
Krystyna Chrzanowska
Martina Simandlová
Lionel Van Maldergem
Philip Stanier
Philip L. Beales
Jean E. Vance
Gudrun E. Moore
UCL Institute of Child Health
Centro Hospitalar e Universitario de Coimbra
University of Alberta
UCL Institute of Neurology
Universidade de Coimbra, Faculdade de Medicina
Mahidol University
Instytut Pomnik-Centrum Zdrowia Dziecka
Fakultni Nemocnice v Motole
Universite de Franche-Comte
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Jan-2014
Citation: Nature Genetics. Vol.46, No.1 (2014), 70-76
Abstract: Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism. © 2014 Nature America, Inc.
ISSN: 15461718
Appears in Collections:Scopus 2011-2015

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