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首页> 美国卫生研究院文献>Wiley-Blackwell Online Open >Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function
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Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

机译：PPP1R21中功能变异的双等位基因缺失会导致内吞功能受损的神经发育综合征

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Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.
机译：下一代测序（NGS）在解决罕见遗传疾病（尤其是神经发育综合症）的遗传基础方面发挥了作用。但是，功能检查对于精确的表型定义和了解潜在的疾病机制至关重要。使用全外显子组（WES）和全基因组测序（WGS）在四个独立的家族中出现肌张力低下，神经发育延迟，面部畸形，白质丢失和and体变薄，我们鉴定了四个以前未报道的纯合截断的PPP1R21等位基因：c。 347delT p。（Ile116Lysfs * 25），c.2170_2171ins GGTA p。（Ile724Argfs * 8），c.1607dupT p。（Leu536Phefs * 7），c.2063delA p。（Lys688Serfs * 26），发现成纤维细胞中不存在PPP1R21。受影响的个体，支持等位基因丧失功能。 PPP1R21的功能尚未进行过研究，只是大规模的亲和蛋白质组学方法提示与Joubert综合征中PIBF1缺陷的相互作用。我们的免疫共沉淀研究没有证实这一点，但相反定义了PPP1R21在早期内体中的定位。与亚细胞表达模式和表现出贮藏病特征的临床表型一致，我们发现患者成纤维细胞的转铁蛋白-488清除延迟，而摄取正常。总之，我们描述了由双等位基因PPP1R21功能变体缺失引起的新型神经发育综合征，并提出了PPP1R21在内体分类过程或内体成熟途径中的作用。

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