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
© The Korean Society for Laboratory Medicine..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
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| Enthalten in: |
Annals of laboratory medicine - 40(2020), 3 vom: 23. Mai, Seite 224-231 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Song, Ju Sun [VerfasserIn] |
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| Links: |
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| Themen: |
CDH23 protein, human |
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| Anmerkungen: |
Date Completed 27.05.2020 Date Revised 04.12.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.3343/alm.2020.40.3.224 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304593133 |
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| 100 | 1 | |a Song, Ju Sun |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a 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 |
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| 500 | |a Date Completed 27.05.2020 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Korean Society for Laboratory Medicine. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: A heterozygous variant of USH1C that interferes with the interaction between cdh23 and harmonin causes novel AD-NSHL | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Harmonin | |
| 650 | 4 | |a Heterozygous variant | |
| 650 | 4 | |a Nonsyndromic hearing loss | |
| 650 | 4 | |a USH1C | |
| 650 | 7 | |a CDH23 protein, human |2 NLM | |
| 650 | 7 | |a Cadherin Related Proteins |2 NLM | |
| 650 | 7 | |a Cadherins |2 NLM | |
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| 650 | 7 | |a USH1C protein, human |2 NLM | |
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| 700 | 1 | |a Petit, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Sang Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Moon, Il Joon |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jinhyuk |e verfasserin |4 aut | |
| 700 | 1 | |a Ki, Change Seok |e verfasserin |4 aut | |
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