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Ann Lab Med. 2020 May;40(3):224-231. English. Original Article. https://doi.org/10.3343/alm.2020.40.3.224
Song JS , Bahloul A , Petit C , Kim SJ , Moon IJ , Lee J , Ki CS .
GC Genome, Yongin, Korea. changski.md@gmail.com
Unité de génétique et physiologie de l'audition, Institut Pasteur, Paris, France.
UMRS 1120, Inserm, Paris, France.
Sorbonne Universités, Paris, France.
Department of Otolaryngology - Head and Neck Surgery, Stanford University, Stanford, California, USA.
College de France and Institut Pasteur, Paris, France.
Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
Department 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.

Copyright © 2019. Korean Association of Medical Journal Editors.