#619174
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-117 (DFNB117) is caused by homozygous mutation in the CLRN2 gene (618988) on chromosome 4p15.
Autosomal recessive deafness-117 (DFNB117) is characterized by nonsyndromic bilateral moderate-to-profound sensorineural deafness, with onset in early childhood (Vona et al., 2021).
Vona et al. (2021) studied a consanguineous Iranian family in which a brother and sister and a male cousin had nonsyndromic bilateral moderate-to-profound sensorineural hearing loss. Age of onset was reported to be between 2 to 3 years of age, although the authors noted that newborn screening was not routinely performed at the time of these individuals' births. Intrafamilial variability was evident, with the 29-year-old sister showing a downsloping audiogram and moderate-to-profound deafness, whereas her 44-year-old brother had moderate-to-severe hearing loss with slightly better hearing at higher frequencies. Speech recognition thresholds for the sister were 80 and 75 dB at 84% and 88% for right and left ears, respectively, and a 'most comfortable' level of 95 dB. Speech recognition thresholds for her brother were 75 and 80 dB, each at 84%, for right and left ears, respectively. Tympanograms were normal, and the affected individuals had normal neuromotor, speech, and language development, and did not show signs of impaired balance.
Mendia et al. (2024) reported an Iranian man who had hearing impairment starting at 9 to 10 years of age that was slowly progressive. At 51 years of age, he had moderate to severe sensorineural hearing loss without vestibular abnormalities.
The transmission pattern of DFNB117 in the consanguineous Iranian family reported by Vona et al. (2021) was consistent with autosomal recessive inheritance.
In a consanguineous Iranian family with nonsyndromic deafness, Vona et al. (2021) performed genomewide linkage analysis and obtained a single significant lod score of 3.8 for a 14.96-Mb homozygous region on chromosome 4p.
By whole-exome sequencing in a consanguineous Iranian family with nonsyndromic deafness mapping to chromosome 4p, Vona et al. (2021) identified homozygosity for a missense mutation in the CLRN2 gene (T165K; 618988.0001) that segregated fully with disease and was not found in population frequency databases.
Mendia et al. (2024) identified homozygosity for the T165K mutation in the CLRN2 gene in an Iranian man, born to consanguineous parents, with DFNB117. The mutation was identified by whole-exome sequencing.
Using CRISPR/Cas9, Vona et al. (2021) generated clrn2-deficient zebrafish embryos, which showed significantly reduced responses after sound stimulation. Fluorescent phalloidin staining of hair bundles of the inner ear in the clrn2 mutants showed disrupted hair bundle structure and fewer hair cells compared to controls. In CRISPR/Cas9-engineered homozygous Clrn2-deficient mice, auditory thresholds were very elevated at all frequencies tested, whereas heterozygous mice showed thresholds similar to those of wildtype littermates. Distortion product otoacoustic emission (DPOAE) tests revealed that homozygotes had reduced responses compared to heterozygous or wildtype littermates, suggesting impaired outer hair cell function. Scanning electron microscopy of inner and outer hair cell stereocilia bundles in the homozygous mutants showed the expected U- and V-shape, respectively; however, while the patterning of the bundles appeared normal, the heights of their middle and short row stereocilia were visibly more variable compared with those of wildtype littermates, and many of the short row mechanotransducing stereocilia were missing.
Mendia et al. (2024) treated Clrn -/- knockout mice with an AAV-mediated Clrn2 gene replacement therapy targeted to hair cells. In knockout mice treated at P1, the mice experienced improved hearing that was stable for up to 6 months, normalization of stereocilia organization, preservation of integrity of hair cell bundles, and normalization of MET channel activity as assessed by FM1-43 fluorescent dye uptake. Later treatment of mutant mice at P10 and P14 did not show these same improvements. Treatment of the mutant mice at P1 with an AAV-mediated Clrn2 with a T165K (618988.0001) mutation or a Gly146LysfsTer26 mutation did not rescue the abnormal phenotype, supporting the pathogenicity of these mutations.
Mendia, C., Peineau, T., Zamani, M., Felgerolle, C., Yahiaoui, N., Christophersen, N., Papal, S., Maudoux, A., Maroofian, R., Patni, P., Nouaille, S., Bowl, M. R., Delmaghani, S., Galehdari, H., Vona, B., Dulon, D., Vitry, S., El-Amraoui, A. Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss. Molec. Ther. 32: 800-817, 2024. [PubMed: 38243601, related citations] [Full Text]
Vona, B., Mazaheri, N., Lin, S.-J., Dunbar, L. A., Maroofian, R., Azaiez, H., Booth, K. T., Vitry, S., Rad, A., Ruschendorf, F., Varshney, P., Fowler, B., and 14 others. A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans. Hum. Genet. 140: 915-931, 2021. [PubMed: 33496845, images, related citations] [Full Text]
ORPHA: 90636;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
4p15.32 | Deafness, autosomal recessive 117 | 619174 | Autosomal recessive | 3 | CLRN2 | 618988 |
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-117 (DFNB117) is caused by homozygous mutation in the CLRN2 gene (618988) on chromosome 4p15.
Autosomal recessive deafness-117 (DFNB117) is characterized by nonsyndromic bilateral moderate-to-profound sensorineural deafness, with onset in early childhood (Vona et al., 2021).
Vona et al. (2021) studied a consanguineous Iranian family in which a brother and sister and a male cousin had nonsyndromic bilateral moderate-to-profound sensorineural hearing loss. Age of onset was reported to be between 2 to 3 years of age, although the authors noted that newborn screening was not routinely performed at the time of these individuals' births. Intrafamilial variability was evident, with the 29-year-old sister showing a downsloping audiogram and moderate-to-profound deafness, whereas her 44-year-old brother had moderate-to-severe hearing loss with slightly better hearing at higher frequencies. Speech recognition thresholds for the sister were 80 and 75 dB at 84% and 88% for right and left ears, respectively, and a 'most comfortable' level of 95 dB. Speech recognition thresholds for her brother were 75 and 80 dB, each at 84%, for right and left ears, respectively. Tympanograms were normal, and the affected individuals had normal neuromotor, speech, and language development, and did not show signs of impaired balance.
Mendia et al. (2024) reported an Iranian man who had hearing impairment starting at 9 to 10 years of age that was slowly progressive. At 51 years of age, he had moderate to severe sensorineural hearing loss without vestibular abnormalities.
The transmission pattern of DFNB117 in the consanguineous Iranian family reported by Vona et al. (2021) was consistent with autosomal recessive inheritance.
In a consanguineous Iranian family with nonsyndromic deafness, Vona et al. (2021) performed genomewide linkage analysis and obtained a single significant lod score of 3.8 for a 14.96-Mb homozygous region on chromosome 4p.
By whole-exome sequencing in a consanguineous Iranian family with nonsyndromic deafness mapping to chromosome 4p, Vona et al. (2021) identified homozygosity for a missense mutation in the CLRN2 gene (T165K; 618988.0001) that segregated fully with disease and was not found in population frequency databases.
Mendia et al. (2024) identified homozygosity for the T165K mutation in the CLRN2 gene in an Iranian man, born to consanguineous parents, with DFNB117. The mutation was identified by whole-exome sequencing.
Using CRISPR/Cas9, Vona et al. (2021) generated clrn2-deficient zebrafish embryos, which showed significantly reduced responses after sound stimulation. Fluorescent phalloidin staining of hair bundles of the inner ear in the clrn2 mutants showed disrupted hair bundle structure and fewer hair cells compared to controls. In CRISPR/Cas9-engineered homozygous Clrn2-deficient mice, auditory thresholds were very elevated at all frequencies tested, whereas heterozygous mice showed thresholds similar to those of wildtype littermates. Distortion product otoacoustic emission (DPOAE) tests revealed that homozygotes had reduced responses compared to heterozygous or wildtype littermates, suggesting impaired outer hair cell function. Scanning electron microscopy of inner and outer hair cell stereocilia bundles in the homozygous mutants showed the expected U- and V-shape, respectively; however, while the patterning of the bundles appeared normal, the heights of their middle and short row stereocilia were visibly more variable compared with those of wildtype littermates, and many of the short row mechanotransducing stereocilia were missing.
Mendia et al. (2024) treated Clrn -/- knockout mice with an AAV-mediated Clrn2 gene replacement therapy targeted to hair cells. In knockout mice treated at P1, the mice experienced improved hearing that was stable for up to 6 months, normalization of stereocilia organization, preservation of integrity of hair cell bundles, and normalization of MET channel activity as assessed by FM1-43 fluorescent dye uptake. Later treatment of mutant mice at P10 and P14 did not show these same improvements. Treatment of the mutant mice at P1 with an AAV-mediated Clrn2 with a T165K (618988.0001) mutation or a Gly146LysfsTer26 mutation did not rescue the abnormal phenotype, supporting the pathogenicity of these mutations.
Mendia, C., Peineau, T., Zamani, M., Felgerolle, C., Yahiaoui, N., Christophersen, N., Papal, S., Maudoux, A., Maroofian, R., Patni, P., Nouaille, S., Bowl, M. R., Delmaghani, S., Galehdari, H., Vona, B., Dulon, D., Vitry, S., El-Amraoui, A. Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss. Molec. Ther. 32: 800-817, 2024. [PubMed: 38243601] [Full Text: https://doi.org/10.1016/j.ymthe.2024.01.021]
Vona, B., Mazaheri, N., Lin, S.-J., Dunbar, L. A., Maroofian, R., Azaiez, H., Booth, K. T., Vitry, S., Rad, A., Ruschendorf, F., Varshney, P., Fowler, B., and 14 others. A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans. Hum. Genet. 140: 915-931, 2021. [PubMed: 33496845] [Full Text: https://doi.org/10.1007/s00439-020-02254-z]
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