HGNC Approved Gene Symbol: LOXHD1
Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38): 18:46,476,961-46,657,220 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.1 | Deafness, autosomal recessive 77 | 613079 | Autosomal recessive | 3 |
Grillet et al. (2009) cloned mouse Loxhd1, and by database analysis, they identified human LOXHD1. They also cloned a splice variant of Loxhd1 from a mouse inner ear cDNA library, which encodes a deduced 2,068-amino acid mouse protein made up of 15 polycystin (see 601313)/lipoxygenase (see 607206)/alpha-toxin (PLAT) domains. PLAT domains are about 120 amino acids long, form a beta-sandwich consisting of 2 sheets of 4 strands each, and appear to function in plasma membrane targeting. Grillet et al. (2009) identified LOXHD1 orthologs in vertebrates, cephalochordates, and urochordates, but not in arthropods or nematode. In situ hybridization detected Loxhd1 expression in the developing mouse inner ear at embryonic days 13.5 and 16, but not in any other tissue. At postnatal day 4, expression was detected in cochlear and vestibular hair cells, with highest concentration in the nucleus. Loxhd1 progressively localized to the cytoplasm, and in the adult, Loxhd1 was expressed in hair cells along the length of stereocilia.
Riazuddin et al. (2012) detected expression of LOXHD1 in cultured human corneal endothelial cells. In mouse corneas at postnatal day 120, Loxhd1 was detected both in the corneal epithelium and in the endothelium, but with significantly higher expression in epithelial cells.
Based on conservation between the mouse and human LOXHD1 genes, Grillet et al. (2009) determined that the LOXHD1 gene contains at least 43 exons.
By genomic sequence analysis, Grillet et al. (2009) mapped the LOXHD1 gene to chromosome 18q12-q21.
Autosomal Recessive Deafness 77
In a 5-generation consanguineous Iranian family with nonsyndromic hearing loss mapping to chromosome 18q12-q21 (DFNB77; 613079), Grillet et al. (2009) sequenced the LOXHD1 gene and identified a homozygous mutation (R670X; 613072.0001) in all affected family members tested. Unaffected family members were heterozygous for the mutation, which was not found in 243 controls.
In 9 affected children from 2 unrelated Ashkenazi Jewish families with severe to profound congenital nonprogressive nonsyndromic hearing loss in which linkage to the GJB2 (121011)/GJB6 (604418) genes had been excluded, Edvardson et al. (2011) identified homozygosity for a nonsense mutation in the LOXHD1 gene (R1572X; 613072.0002).
Associations Pending Confirmation
For discussion of a possible role of variation in the LOXHD1 gene in Fuchs endothelial corneal dystrophy mapping to chromosome 18q21 (FECD3; 613267), see 613072.0003.
Using an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, Grillet et al. (2009) developed the 'samba' mouse line that becomes hearing impaired by 3 weeks of age and deaf by 8 weeks of age. Homozygous samba mice showed no other neurologic or vestibular abnormalities, and heterozygous samba mice appeared completely normal. Stereociliary development was not affected in homozygous samba mice, but hair cell function was perturbed and hair cells eventually degenerated. Grillet et al. (2009) found that samba was a mutation in the mouse Loxhd1 gene that destabilized the beta-sandwich structure of PLAT domain 10. The mutation did not alter mRNA or protein stability or localization of Loxhd1 protein along the length of stereocilia. However, by postnatal day 21, some hair cells showed morphologic defects with fused stereocilia and membrane ruffling at the apical cell surface. Profound degenerative changes were obvious by postnatal day 90, including hair cell loss and a reduction in spiral ganglion neurons. Grillet et al. (2009) hypothesized that the degeneration of spiral ganglion neurons was likely secondary to perturbations in the function and maintenance of hair cells.
In affected members of a 5-generation consanguineous Iranian family segregating autosomal recessive nonsyndromic hearing loss (DFNB77; 613079), Grillet et al. (2009) identified homozygosity for a 2008C-T transition in exon 15 of the LOXHD1 gene, resulting in an arg670-to-ter (R670X) substitution at a conserved residue in the C-terminal end of the fifth PLAT domain, predicted to result in either a severely truncated protein or nonsense-mediated mRNA decay. Unaffected members of the family were heterozygous for the mutation, which was not found in 243 controls.
In 9 affected children from 2 unrelated Ashkenazi Jewish families segregating autosomal recessive nonprogressive sensorineural hearing loss (DFNB77; 613079), Edvardson et al. (2011) identified homozygosity for a 4714C-T transition in exon 30, resulting in an arg1572-to-ter (R1572X) substitution in the eleventh PLAT domain. The mutation was present in heterozygosity in the unaffected parents, and 4 heterozygotes were detected among 719 anonymous Ashkenazi individuals, indicating a carrier rate of 1:180 Ashkenazi Jews.
This variant is classified as a variant of unknown significance because its contribution to the phenotype of Fuchs endothelial corneal dystrophy (see FECD3, 613267) has not been confirmed.
Using DNA from 1 affected and 1 unaffected member from each of 3 large families with Fuchs endothelial corneal dystrophy mapping to chromosome 18q21.2-q21.3 (FECD3; 613267), originally studied by Sundin et al. (2006), Riazuddin et al. (2012) analyzed the coding sequence and intron-exon junctions of 134 genes within the most conservative critical region. In 2 of the 3 families, they found no changes that could explain the disorder, but in the third family ('kindred 2' of Sundin et al., 2006), a missense variant in the LOXHD1 gene (R547C; 613072.0003) was found to be present in 7 of 8 affected members of the family, as well as in 1 family member with an unknown affection status. The variant was not detected in 384 chromosomes of individuals over 60 years of age with phenotypically normal corneas on slit-lamp examination; however, it had been identified in an individual of African descent (Bushman) in a whole-genome sequencing project. Riazuddin et al. (2012) analyzed all coding exons of LOXHD1 in a cohort of 207 unrelated individuals with FECD and identified 15 variants in 16 patients which were not found in 384 ethnically matched control chromosomes, in the 1000 Genomes Project, or in the 1500 Exome Project. However, sequencing of all coding exons of LOXHD1 in 288 unrelated unaffected individuals revealed 8 previously unreported variants, and the authors noted that another 12 LOXHD1 variants had previously been identified in 550 samples of European descent in the 1500 Exome Project. Analysis of the data showed significant enrichment of variants (p = 0.003) in cases compared to controls, suggesting that the observed mutational load of this locus is relevant to FECD, but Riazuddin et al. (2012) cautioned that interpreting with confidence the causal potential of any single variant allele was not possible.
Edvardson, S., Jalas, C., Shaag, A., Zenvirt, S., Landau, C., Lerer, I., Elpeleg, O. A deleterious mutation in the LOXHD1 gene causes autosomal recessive hearing loss in Ashkenazi Jews. Am. J. Med. Genet. 155A: 1170-1172, 2011. [PubMed: 21465660] [Full Text: https://doi.org/10.1002/ajmg.a.33972]
Grillet, N., Schwander, M., Hildebrand, M. S., Sczaniecka, A., Kolatkar, A., Velasco, J., Webster, J. A., Kahrizi, K., Najmabadi, H., Kimberling, W. J., Stephan, D., Bahlo, M., Wiltshire, T., Tarantino, L. M., Kuhn, P., Smith, R. J. H., Muller, U. Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans. Am. J. Hum. Genet. 85: 328-337, 2009. [PubMed: 19732867] [Full Text: https://doi.org/10.1016/j.ajhg.2009.07.017]
Riazuddin, S. A., Parker, D. S., McGlumphy, E. J., Oh, E. C., Iliff, B. W., Schmedt, T., Jurkunas, U., Schleif, R., Katsanis, N., Gottsch, J. D. Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy. Am. J. Hum. Genet. 90: 533-539, 2012. [PubMed: 22341973] [Full Text: https://doi.org/10.1016/j.ajhg.2012.01.013]
Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C. L., Stark, W. J., Gottsch, J. D. A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32. Invest. Ophthal. Vis. Sci. 47: 3919-3926, 2006. [PubMed: 16936105] [Full Text: https://doi.org/10.1167/iovs.05-1619]