HGNC Approved Gene Symbol: STRC
Cytogenetic location: 15q15.3 Genomic coordinates (GRCh38): 15:43,599,563-43,618,800 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.3 | Deafness, autosomal recessive 16 | 603720 | Autosomal recessive | 3 |
The STRC gene encodes stereocilin, a large extracellular structural protein found in the stereocilia of outer hair cells in the inner ear. It is associated with horizontal top connectors and the tectorial membrane attachment crowns that are important for proper cohesion and positioning of the stereociliary tips (Verpy et al., 2001; summary by Francey et al., 2012).
To identify genes mutated in hereditary deafness, Verpy et al. (2001) developed a candidate gene approach based on the identification of genes specifically or preferentially expressed in the inner ear. They identified a mouse clone derived from a vestibular library that was homologous to several human genomic clones derived from the 15q15 chromosomal region, within the locus for DFNB16. The human STRC protein is made up of 1,809 amino acids and contains a putative signal peptide and several hydrophobic segments. Using immunohistolabeling, Verpy et al. (2001) demonstrated that, in the mouse inner ear, stereocilin is expressed only in the sensory hair cells and is associated with the stereocilia, the stiff microvilli forming the structure for mechanoreception of sound stimulation.
The STRC gene contains 29 exons, encompassing approximately 19 kb, and is tandemly duplicated, with the coding sequence of the second copy interrupted by a stop codon in exon 20 (Verpy et al., 2001). The 2 copies are in a telomere-to-centromere orientation, less than 100 kb apart.
Verpy et al. (2001) identified the STRC gene on chromosome 15q15, within the candidate region for DFNB16.
Pseudogene
STRC lies in a complex genomic region characterized by a large segmental duplication that includes a STRC pseudogene with a coding sequence that is 99.6% conserved (summary by Francey et al., 2012).
Autosomal Recessive Deafness 16
In affected members of a consanguineous Pakistani family with autosomal recessive nonsyndromic sensorineural deafness-16 (DFNB16; 603720), Verpy et al. (2001) identified a homozygous truncating mutation in the STRC gene (606440.0001). Affected members of a French family with the disorder were compound heterozygous for a frameshift mutation (606440.0002) and a large deletion (606440.0003) in the copy of the STRC gene containing 29 coding exons.
Francey et al. (2012) used 3 different genotyping array platforms and Sanger sequencing to analyze 659 GJB2 (121011) mutation-negative pediatric probands with sensorineural hearing loss. Using both array genotyping information and sequencing data, the authors identified 17 STRC deletions, including 7 homozygous and 9 heterozygous deletions; with sequencing data alone in 2 patient, they identified 1 heterozygous deletion. After sequencing for point mutations, they found that 6 of 9 probands with a heterozygous deletion carried a novel variant in the STRC gene; 4 of the variants were confirmed by parental analysis to be on the trans allele. All patients with biallelic STRC alterations had mild to moderate hearing loss. The findings suggested that STRC may be a common contributor to nonsyndromic sensorineural hearing loss. Functional studies of the deletions and variants were not performed.
In 4 unrelated children with DFNB16, Vona et al. (2015) identified biallelic alterations in the STRC gene. Three patients were compound heterozygous for a gene deletion and a putative pathogenic point mutation, and 1 was compound heterozygous for 2 putative pathogenic point mutations. Functional studies of the variants were not performed. The patients were ascertained from a larger cohort of 94 GJB2 (121011)/GJB6 (604418)-negative pediatric patients with sensorineural hearing loss who underwent genetic analysis. Vona et al. (2015) emphasized the difficulties in technical detection, evaluation, and interpretation of deletions and mutations in the STRC gene.
Deafness-Infertility Syndrome
Dgany et al. (2002) reported a French family in which a 56-year-old male and his 2 brothers suffered from type I congenital dyserythropoietic anemia (CDA1; 224120), asthenoteratozoospermia, and nonsyndromic deafness. They identified homozygosity for a point mutation within the codanin gene (N598S; 607465.0003) as the cause of the type I CDA. Avidan et al. (2003) found that the 3 sibs were also homozygous for an approximately 70-kb deletion in chromosome 15q15, which removed the entire stereocilin gene and truncated the CATSPER2 gene (607249). Avidan et al. (2003) suggested that lack of functional stereocilin, which is mutated in nonsyndromic sensorineural deafness, and CATSPER2, a voltage-gated cation channel expressed exclusively in spermatozoa, may explain the observed deafness and male infertility phenotypes (611102), respectively.
In 3 consanguineous Iranian families segregating nonsyndromic deafness and male infertility, Zhang et al. (2007) identified an approximately 100-kb deleted region on chromosome 15q15.3 involving KIAA0377 (610979), CKMT1B (123290), STRC, and CATSPER2. The families did not have identical deletions and haplotype analysis indicated that the families did not share a common ancestor; the authors noted that a large tandem repeat on chromosome 15q15.3 makes it prone to rearrangement. Zhang et al. (2007) stated that the hearing loss phenotype in these families was similar by audioprofiling to that of DFNB16, suggesting that deletion of STRC is causally related to their deafness.
Vona et al. (2015) reported 3 patients, including 2 boys and a girl, with onset of sensorineural deafness between birth and early childhood. All had homozygous deletions of the STRC and CATSPER2 genes. All were prepubertal at the time of study and were not evaluated for fertility. One boy had additional congenital abnormalities and comorbidities, which were likely independent of the deafness. The patients were ascertained from a larger cohort of 94 GJB2/GJB6-negative pediatric patients with sensorineural hearing loss who underwent genetic analysis.
Verpy et al. (2008) detected stereocilin in association with horizontal top connectors, lateral links that join adjacent stereocilia within the outer hair cell's hair bundle. The authors found that these links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, Verpy et al. (2008) concluded that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic nonlinear behavior of the mechanoelectrical transducer channel.
In affected members of a consanguineous Pakistani family with autosomal recessive nonsyndromic sensorineural deafness-16 (DFNB16; 603720), Verpy et al. (2001) identified a homozygous 1-bp insertion (c.3157_3158insC) in exon 13 of the STRC gene. The insertion was expected to result in the translocation of 19 out-of-frame amino acids and a downstream premature termination codon at position 3214 in exon 13.
In affected members of a family with autosomal recessive deafness-16 (DFNB16; 603720), Verpy et al. (2001) identified compound heterozygous deletions in the STRC gene: a 4-bp deletion in exon 5 (c.2171_2174delTTTG) inherited from the father, and a larger deletion encompassing exons 17 to 29 (606440.0003) inherited from the mother. The 4-bp deletion was predicted to result in the translation of 5 out-of-frame amino acids and a downstream premature termination codon at position 2185 in exon 5. The authors located the 5-prime boundary of the larger deletion between intron 7 and the 3-prime end of intron 16, and the 3-prime boundary downstream of the most 3-prime exon, indicating that the deletion extended at least from exons 17 through 29.
For discussion of a deletion of exons 17 through 29 in the STRC gene that was found in compound heterozygous state in affected members of a family with autosomal recessive nonsyndromic sensorineural deafness-16 (DFNB16; 603720) by Verpy et al. (2001), see 606440.0002.
Avidan, N., Tamary, H., Dgany, O., Cattan, D., Pariente, A., Thulliez, M., Borot, N., Moati, L., Barthelme, A., Shalmon, L., Krasnov, T., Ben-Asher, E., and 9 others. CATSPER2, a human autosomal nonsyndromic male infertility gene. Europ. J. Hum. Genet. 11: 497-502, 2003. [PubMed: 12825070] [Full Text: https://doi.org/10.1038/sj.ejhg.5200991]
Dgany, O., Avidan, N., Delaunay, J., Krasnov, T., Shalmon, L., Shalev, H., Eidelitz-Markus, T., Kapelushnik, J., Cattan, D., Pariente, A., Tulliez, M., Cretien, A., and 13 others. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am. J. Hum. Genet. 71: 1467-1474, 2002. [PubMed: 12434312] [Full Text: https://doi.org/10.1086/344781]
Francey, L. J., Conlin, L. K., Kadesch, H. E., Clark, D., Berrodin, D., Sun, Y., Glessner, J., Hakonarson, H., Jalas, C., Landau, C., Spinner, N. B., Kenna, M., Sagi, M., Rehm, H. L., Krantz, I. D. Genome-wide SNP genotyping identifies the stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment. Am. J. Med. Genet. 158A: 298-308, 2012. [PubMed: 22147502] [Full Text: https://doi.org/10.1002/ajmg.a.34391]
Verpy, E., Masmoudi, S., Zwaenepoel, I., Leibovici, M., Hutchin, T. P., Del Castillo, I., Nouaille, S., Blanchard, S., Laine, S., Popot, J.-L., Moreno, F., Mueller, R. F., Petit, C. Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus. Nature Genet. 29: 345-349, 2001. [PubMed: 11687802] [Full Text: https://doi.org/10.1038/ng726]
Verpy, E., Weil, D., Leibovici, M., Goodyear, R. J., Hamard, G., Houdon, C., Lefevre, G. M., Hardelin, J.-P., Richardson, G. P., Avan, P., Petit, C. Stereocilin-deficient mice reveal the origin of cochlear waveform distortions. Nature 456: 255-258, 2008. [PubMed: 18849963] [Full Text: https://doi.org/10.1038/nature07380]
Vona, B., Hofrichter, M. A. H., Neuner, C., Schroder, J., Gehrig, A., Hennermann, J. B., Kraus, F., Shehata-Dieler, W., Klopocki, E., Nanda, I., Haaf, T. DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics. Clin. Genet. 87: 49-55, 2015. [PubMed: 26011646] [Full Text: https://doi.org/10.1111/cge.12332]
Zhang, Y., Malekpour, M., Al-Madani, N., Kahrizi, K., Zanganeh, M., Lohr, N. J., Mohseni, M., Mojahedi, F., Daneshi, A., Najmabadi, H., Smith, R. J. H. Sensorineural deafness and male infertility: a contiguous gene deletion syndrome. J. Med. Genet. 44: 233-240, 2007. Note: Erratum: J. Med. Genet. 44: 544 only, 2007. [PubMed: 17098888] [Full Text: https://doi.org/10.1136/jmg.2006.045765]