Ann Lab Med.  2020 May;40(3):224-231. 10.3343/alm.2020.40.3.224.

A Novel Heterozygous Missense Variant (c.667G>T;p.Gly223Cys) in USH1C That Interferes With Cadherin-Related 23 and Harmonin Interaction Causes Autosomal Dominant Nonsyndromic Hearing Loss

Affiliations
  • 1GC Genome, Yongin, Korea. changski.md@gmail.com
  • 2Unité de génétique et physiologie de l'audition, Institut Pasteur, Paris, France.
  • 3UMRS 1120, Inserm, Paris, France.
  • 4Sorbonne Universités, Paris, France.
  • 5Department of Otolaryngology - Head and Neck Surgery, Stanford University, Stanford, California, USA.
  • 6College de France and Institut Pasteur, Paris, France.
  • 7Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 8Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 9Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
  • 10Department of Bioinformatics, University of Sciences and Technology, Daejeon, Korea.

Abstract

BACKGROUND
Pathogenic variants of USH1C, encoding a PDZ-domain-containing protein called harmonin, have been known to cause autosomal recessive syndromic or nonsyndromic hearing loss (NSHL). We identified a causative gene in a large Korean family with NSHL showing a typical pattern of autosomal dominant (AD) inheritance.
METHODS
Exome sequencing was performed for five affected and three unaffected individuals in this family. Following identification of a candidate gene variant, segregation analysis and functional studies, including circular dichroism and biolayer interferometry experiments, were performed.
RESULTS
A novel USH1C heterozygous missense variant (c.667G>T;p.Gly223Cys) was shown to segregate with the NSHL phenotype in this family. This variant affects an amino acid residue located in the highly conserved carboxylate-binding loop of the harmonin PDZ2 domain and is predicted to disturb the interaction with cadherin-related 23 (cdh23). The affinity of the variant PDZ2 domain for a biotinylated synthetic peptide containing the PDZ-binding motif of cdh23 was approximately 16-fold lower than that of the wild-type PDZ2 domain and that this inaccessibility of the binding site was caused by a conformational change in the variant PDZ2 domain.
CONCLUSIONS
A heterozygous variant of USH1C that interferes with the interaction between cdh23 and harmonin causes novel AD-NSHL.

Keyword

Harmonin; Nonsyndromic hearing loss; USH1C; Heterozygous variant

MeSH Terms

Binding Sites
Circular Dichroism
Exome
Hearing Loss*
Hearing*
Humans
Interferometry
Phenotype
Wills
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