Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

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.

Source: The American Journal of Human Genetics - February 8, 2018 Category: Genetics & Stem Cells Authors: Clothilde Esteve, Ludmila Francescatto, Perciliz L. Tan, Aur élie Bourchany, Cécile De Leusse, Evelyne Marinier, Arnaud Blanchard, Patrice Bourgeois, Céline Brochier-Armanet, Ange-Line Bruel, Arnauld Delarue, Yannis Duffourd, Emmanuelle Ecochard-Dugela Tags: Article Source Type: research