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Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome

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.

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Figure 1: Clinical and radiological manifestations of individuals with LMS.
Figure 2: Overview of phosphatidylserine metabolism and the PSS1 protein.
Figure 3: Phosphatidylserine synthesis is increased in cultured fibroblasts from individuals with LMS compared to control fibroblasts.
Figure 4: Phosphatidylserine synthase activity in fibroblasts from individuals with LMS is resistant to inhibition by phosphatidylserine, whereas PSS1 mRNA and protein expression, PSS2 mRNA expression and total cellular aminophospholipid content are normal.
Figure 5: Overexpression of mutant PTDSS1 RNA in zebrafish embryos disrupts normal development.

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Acknowledgements

We are grateful to the individuals with LMS and their families for their participation in this study. We thank P. Clayton and R. Hennekam for their comments on the manuscript, A. Offiah for confirming the radiological diagnosis in subject 1 and W. Emmett for his valuable help in processing raw sequencing data. The authors would like to acknowledge D. Trabzuni and the UK Brain Expression Consortium, the Human Brain Transcriptome project at the Department of Neurobiology at the Yale University School of Medicine NHLBI for the use of data from their public database and the GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison, including the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). S.B.S. was supported by the Fundação para a Ciência e Tecnologia (SFRH/BD/46778/2008). The Centre for Translational Genomics–GOSgene is supported by the Biomedical Research Centre of the National Institute for Health Research at Great Ormond Street Hospital for Children NHS Foundation Trust and UCL Institute of Child Health. D.J. was supported by a Wellcome Trust ViP Award. D.W. is a recipient of Research Career Development Awards from the Faculty of Medicine at Ramathibodi Hospital. M.S. is supported by Czech research development grant 00064203. P.S. is supported by the Great Ormond Street Hospital Children's Charity (GOSHCC). The Fetal Growth and Development research team of G.E.M. is funded by WellBeing of Women, the Wellcome Trust, GOSHCC and the UK Medical Research Council. The research of J.E.V. is supported by the National Science and Engineering Council of Canada.

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S.B.S. and G.E.M. designed the study. S.B.S., A.B., R.S., A.C., J.S., J.M.S., D.W., K.C., M.S. and L.V.M. characterized individuals with LMS and collected clinical data and samples. S.B.S. designed and performed direct mutagenesis, zebrafish experiments, Sanger sequencing and cell culture and wrote the manuscript. D.J. designed and performed zebrafish experiments and wrote the manuscript. E.C. designed and performed next-generation sequencing data analysis and segregation studies and wrote the manuscript. J.E.V. and G.T. designed and performed phospholipid metabolism studies and wrote the manuscript. M.I. performed RT-qPCR experiments. G.A. performed electron microscopy studies. M.R. contributed data for human adult brain transcriptome analysis. J.D. and P.S. performed Annexin V staining experiments. P.S. and P.L.B. contributed to experimental design and data analysis. All authors discussed the results and implications of the work and commented on the manuscript.

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Correspondence to Sérgio B Sousa.

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Sousa, S., Jenkins, D., Chanudet, E. et al. Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nat Genet 46, 70–76 (2014). https://doi.org/10.1038/ng.2829

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