HGNC Approved Gene Symbol: GRXCR1
Cytogenetic location: 4p13 Genomic coordinates (GRCh38) : 4:42,892,713-43,030,658 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p13 | Deafness, autosomal recessive 25 | 613285 | Autosomal recessive | 3 |
Schraders et al. (2010) cloned human GRXCR1, which encoded a deduced 290-amino acid protein containing a putative glutaredoxin catalytic domain and a cysteine-rich C-terminal region. The glutaredoxin domain is predicted to function in the reversible S-glutathionylation of proteins. Quantitative PCR detected high GRXCR1 expression in fetal cochlea, moderate expression in adult testis, low expression in fetal heart and adult duodenum and brain, and little to no expression in other adult and fetal tissues examined.
Hunker et al. (2005) stated that the mouse Grxcr1 gene contains 290 amino acids. They found that transfected Grxcr1 was closely associated with actin filament-like structures on the dorsal/apical surface of cultured cells.
Odeh et al. (2010) found that 2 groups of 4 cysteines in the C-terminal cysteine-rich domain of mouse Grxcr1 were predicted to fold into a zinc finger configuration. They found that the central glutaredoxin-like domain and cysteine-rich C terminus of GRXCR1 was highly conserved between vertebrates. Grxcr1 was expressed in sensory epithelial of the mouse inner ear and localized along the length of stereocilia of auditory and vestibular hair cells in mouse cochlear explants. It also localized along the length of actin filament-rich structures in filopodia in monkey fibroblasts and in microvilli at the apical surface of porcine kidney epithelial cells.
Schraders et al. (2010) determined that the GRXCR1 gene contains 4 exons.
Schraders et al. (2010) mapped the GRXCR1 gene to chromosome 4p13. Odeh et al. (2004) mapped the mouse pirouette (pi) locus, containing the Grxcr1 gene, to a region of mouse chromosome 5 that shares syntenic homology with human chromosome 4.
In 3 sibs from a nonconsanguineous Dutch family, 1 sporadic Dutch patient, and affected members of 2 consanguineous Pakistani families with autosomal recessive nonsyndromic hearing loss (DFNB25; 613285) mapping to 4p13, Schraders et al. (2010) identified homozygosity for 1 missense, 1 nonsense, and 2 splice site mutations in the GRXCR1 gene (613283.0001-613283.0004, respectively) that cosegregated with disease and were not found in 180 Dutch or 240 Pakistani controls.
Pirouette (pi) is an autosomal recessive mutation that arose spontaneously in the C3H inbred strain of mice. Pi/pi mice are fertile and have a normal life span. They show circling, head-tossing behavior, and hyperactivity, and develop profound hearing loss in the early postnatal period. Sensory hair cells in the organ of Corti in pi/pi mice show early degeneration, and beyond 1 month of age, pi/pi mice exhibit degeneration of other cell types, including spinal ganglion and cells in the stria vascularis. Odeh et al. (2004) found that pi and 2 additional strains of mice with inner ear dysfunction, transgenic line 370 (pi-tg370) and Tasmanian devil (pi-tde), represent 3 independent allelic mutations at the pi locus. Hunker et al. (2005) reported that pi is a mutation of the mouse Grxcr1 gene.
Odeh et al. (2010) identified 2 additional mouse strains, nm2766 (pi-2j) and nm3325 (pi-3j), that exhibit similar vestibular and auditory deficits due to spontaneous recessive mutations in the Grxcr1 gene. Odeh et al. (2010) showed that loss of Grxcr1 function in pirouette mice resulted in abnormally thin and slightly shortened stereocilia.
In 3 affected sibs from a nonconsanguineous Dutch family with autosomal recessive deafness-25 (613285), Schraders et al. (2010) identified homozygosity for a splice site mutation (628-9C-A) in intron 2 of the GRXCR1 gene, predicted to create a different splice acceptor site. The mutation was not found in unaffected family members or in 180 Dutch controls. Analysis of GRXCR1 cDNA from 2 of the affected sibs demonstrated the presence of 7 additional base pairs between exons 2 and 3, leading to a frameshift and a premature stop codon.
In a sporadic case of autosomal recessive deafness-25 (613285) in a Dutch patient, Schraders et al. (2010) identified homozygosity for a splice site mutation (627+19A-T) in intron 2 of the GRXCR1 gene, predicted to create an additional donor splice site. The mutation was not found in unaffected family members or in 180 Dutch controls.
In affected members of a consanguineous Pakistani family with autosomal recessive deafness-25 (613285), Schraders et al. (2010) identified homozygosity for a 229C-T transition in the GRXCR1 gene, resulting in a gln77-to-ter (Q77X) substitution. The mutation was not found in unaffected family members or in 240 Pakistani controls.
In affected members of a consanguineous Pakistani family with autosomal recessive deafness-25 (613285), Schraders et al. (2010) identified homozygosity for a 412C-T transition in exon 2 of the GRXCR1 gene, resulting in an arg138-to-cys (R138C) substitution at a highly conserved residue. The mutation was not found in unaffected family members or in 240 Pakistani controls.
Hunker, K., Odeh, H., Zheng, L., Barald, K., Raphael, Y., Bartles, J., Kohrman, D. Expression and mutation analysis of Grxcr1, the gene affected in the mouse deafness mutant pirouette. (Abstract) ARO Abstracts 28: 279 only, 2005.
Odeh, H., Hagiwara, N., Skynner, M., Mitchem, K. L., Beyer, L. A., Allen, N. D., Brilliant, M. H., Lebart, M. C., Dolan, D. F., Raphael, Y., Kohrman, D. C. Characterization of two transgene insertional mutations at pirouette, a mouse deafness locus. Audiol. Neurootol. 9: 303-314, 2004. [PubMed: 15347914] [Full Text: https://doi.org/10.1159/000080701]
Odeh, H., Hunker, K. L., Belyantseva, I. A., Azaiez, H., Avenarius, M. R., Zheng, L., Peters, L. M., Gagnon, L. H., Hagiwara, N., Skynner, M. J., Brilliant, M. H., Allen, N. D., Riazuddin, S., Johnson, K. R., Raphael, Y., Najmabadi, H., Friedman, T. B., Bartles, J. R., Smith, R. J. H., Kohrman, D. C. Mutations in Grxcr1 are the basis for inner ear dysfunction in the pirouette mouse. Am. J. Hum. Genet. 86: 148-160, 2010. [PubMed: 20137774] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.016]
Schraders, M., Lee, K., Oostrik, J., Huygen, P. L. M., Ali, G., Hoefsloot, L. H., Veltman, J. A., Cremers, F. P. M., Basit, S., Ansar, M., Cremers, C. W. R. J., Kunst, H. P. M., Ahmad, W., Admiraal, R. J. C., Leal, S. M., Kremer, H. Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment. Am. J. Hum. Genet. 86: 138-147, 2010. [PubMed: 20137778] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.017]