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

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.

Keywords: GCUNC-45.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Bone and Bones / pathology*
  • Child, Preschool
  • Cholestasis / genetics*
  • Diarrhea / genetics*
  • Diarrhea / physiopathology
  • Family
  • Female
  • Fibroblasts / pathology
  • Gastrointestinal Motility
  • Hearing Loss / genetics*
  • Humans
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Loss of Function Mutation / genetics*
  • Lymphocytes / pathology
  • Male
  • Pedigree
  • Phenotype
  • Syndrome
  • Young Adult
  • Zebrafish


  • Intracellular Signaling Peptides and Proteins
  • UNC45A protein, human