Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome
| Autor: | Mina Ryten, Sérgio B. Sousa, Richard H Scott, Estelle Chanudet, Glenn Anderson, Lionel Van Maldergem, Dagan Jenkins, Philip L. Beales, Krystyna H. Chrzanowska, James Docker, Jorge M. Saraiva, Philip Stanier, Gudrun E. Moore, Miho Ishida, Angela Barnicoat, Joaquim Sá, Martina Simandlova, Duangrurdee Wattanasirichaigoon, Guergana Tasseva, Jean E. Vance, Alistair Calder |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Fosfatidilserinas Embryo Nonmammalian Adolescent Nitrogenous Group Transferases Molecular Sequence Data Dwarfism Phosphatidylserines Biology medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics medicine Animals Humans Missense mutation Abnormalities Multiple Child Gene Cells Cultured Zebrafish 030304 developmental biology Transferases de Grupos Nitrogenados Phosphatidylethanolamine 0303 health sciences Mutation Deficiência Intelectual Syndrome Phosphatidylserine Fibroblasts Hyperostosis medicine.disease 3. Good health chemistry Craniotubular Hyperostosis Female Anomalias Congénitas Múltiplas 030217 neurology & neurosurgery Cutis laxa |
| Zdroj: | Nature Genetics. 46:70-76 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng.2829 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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