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.

• MeSH
• dánio pruhované embryologie   genetika   MeSH
• dítě MeSH
• embryo nesavčí MeSH
• fibroblasty metabolismus   MeSH
• fosfatidylseriny biosyntéza   genetika   MeSH
• hyperostóza MeSH
• kultivované buňky MeSH
• lidé MeSH
• mladiství MeSH
• mnohočetné abnormality genetika   MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• nanismus MeSH
• syndrom MeSH
• transferasy dusíkatých skupin genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH