Taylor S Paige, Dantas Tiago J, Duran Ivan, Wu Sulin, Lachman Ralph S, Nelson Stanley F, Cohn Daniel H, Vallee Richard B, Krakow Deborah
Department of Human Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA.
Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
Nat Commun. 2015 Jun 16;6:7092. doi: 10.1038/ncomms8092.
The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs and polydactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify an additional SRPS gene and further unravel the functional basis for IFT. We perform whole-exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable length, including hyperelongated, cilia, Hedgehog pathway impairment and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation and skeletogenesis.
短肋多指综合征(SRPSs)是一组常染色体隐性、围产期致死性骨骼疾病,具有异质性,主要特征为短而水平的肋骨、短肢和多指。影响鞭毛内运输(IFT)的多个基因发生突变会导致SRPS,但并非所有病例都是由这些基因突变引起的。在此,我们鉴定出另一个SRPS基因,并进一步阐明了IFT的功能基础。我们进行了全外显子组测序,在一个新的致病基因——胞质动力蛋白2轻中间链1(DYNC2LI1)中发现了突变,该突变在三个家系中与疾病共分离。利用原代成纤维细胞,我们发现DYNC2LI1对动力蛋白2复合体的稳定性至关重要,并且DYNC2LI1的突变会导致纤毛长度可变,包括超长纤毛、Hedgehog信号通路受损以及纤毛内IFT积累。本研究的结果拓展了我们对SRPS基因座异质性的认识,并证明了DYNC2LI1在动力蛋白2复合体稳定性、纤毛功能、Hedgehog信号调节和骨骼发生中的重要性。