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
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| ID: wpr-785397
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WPRO
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.Palabras clave
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Asunto principal:
Fenotipo
/
Testamentos
/
Sitios de Unión
/
Dicroismo Circular
/
Exoma
/
Audición
/
Pérdida Auditiva
/
Interferometría
Tipo de estudio:
Etiology_studies
Límite:
Humans
Idioma:
En
Revista:
Annals of Laboratory Medicine
Año:
2020
Tipo del documento:
Article