Ann Lab Med 2020; 40(3): 224-231
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
Ju Sun Song, M.D.1,*, Amel Bahloul, Ph.D.2,3,4,5,*, Christine Petit, M.D., Ph.D.2,3,4,6, Sang Jin Kim, M.D., Ph.D.7, Il Joon Moon, M.D., Ph.D.8, Jinhyuk Lee, Ph.D.9,10, and Change-Seok Ki, M.D., Ph.D.1
1GC Genome, Yongin, Korea; 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
Corresponding author: Chang-Seok Ki, M.D., Ph.D.
GC Genome, 107 Ihyeon-ro 30beon-gil, Giheung-gu, Yongin 16924, Korea
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* These authors contributed equally to this work.
Received: June 13, 2019; Revised: August 23, 2019; Accepted: November 26, 2019; Published online: May 1, 2020.
© Korean Society for Laboratory Medicine. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: Harmonin, Nonsyndromic hearing loss, USH1C, Heterozygous variant

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