1] Clinical and Molecular Genetics Unit, University College London (UCL) Institute of Child Health, London, UK. [2] Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
1] Molecular Medicine Unit, UCL Institute of Child Health, London, UK. [2].
Nat Genet. 2014 Jan;46(1):70-6. doi: 10.1038/ng.2829. Epub 2013 Nov 17.
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.
伦茨-马耶斯基综合征（LMS）是一种智力残疾和多种先天性异常的综合征，其特征为广泛的颅管状骨过度增生。通过使用全外显子组测序并选择与预测的 LMS 显性新生病因一致的变体，我们在编码磷酸丝氨酸合酶 1（PSS1）的 PTDSS1 中发现了致病的杂合错义突变。PSS1 是参与磷酸丝氨酸生成的两种酶之一。受影响个体的完整成纤维细胞中的磷酸丝氨酸合成增加，并且磷酸丝氨酸对 PSS1 的终产物抑制作用明显降低。因此，这些突变导致与 PSS1 的调节功能障碍相关的功能获得效应。据我们所知，我们已将 LMS 确定为首个由磷脂酰丝氨酸代谢紊乱引起的人类疾病。我们的研究结果表明，在磷脂酰丝氨酸合成和骨代谢之间存在一个尚未被探索的联系。
