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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
Annals of Laboratory Medicine ; : 224-231, 2020.
Article in English | WPRIM | ID: wpr-785397
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.
Subject(s)

Full text: Available Index: WPRIM (Western Pacific) Main subject: Phenotype / Wills / Binding Sites / Circular Dichroism / Exome / Hearing / Hearing Loss / Interferometry Type of study: Etiology study Limits: Humans Language: English Journal: Annals of Laboratory Medicine Year: 2020 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Phenotype / Wills / Binding Sites / Circular Dichroism / Exome / Hearing / Hearing Loss / Interferometry Type of study: Etiology study Limits: Humans Language: English Journal: Annals of Laboratory Medicine Year: 2020 Type: Article