Aix Marseille Univ, INSERM, MMG, 13385 Marseille, France.
Center for Human Disease Modeling, Duke University, Durham, NC, USA.
Am J Hum Genet. 2018 Mar 1;102(3):364-374. doi: 10.1016/j.ajhg.2018.01.009. Epub 2018 Feb 8.
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
尽管我们已经迅速发现了许多罕见遗传疾病的相关基因，但仍然会遇到一些具有综合征表现的个体。在这里，我们研究了三个家系中的 4 位受影响个体，他们均表现出胆汁淤积、先天性腹泻、听力受损和骨骼脆弱等症状。对所有受影响个体及其父母进行外显子组测序，发现 Unc-45 肌球蛋白伴侣 A (UNC45A) 中的双等位基因突变可能是导致这种疾病的原因。对候选基因的后续体外和体内功能研究表明，该基因发生功能丧失性突变，从而导致蛋白活性减弱或丧失，同时伴有肠道发育和功能缺陷。
