Alternative titles; symbols
HGNC Approved Gene Symbol: ALDH1A3
Cytogenetic location: 15q26.3 Genomic coordinates (GRCh38): 15:100,879,831-100,916,626 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.3 | Microphthalmia, isolated 8 | 615113 | Autosomal recessive | 3 |
Hsu et al. (1994) identified and characterized the ALDH6 gene. The existence of this unique ALDH isozyme in human saliva and its polymorphism had previously been demonstrated. The ALDH6 cDNA is 3,457 bp long and contains an open reading frame encoding 512 amino acids. The deduced amino acid sequence shows that the protein is larger than human liver ALDH1 (100640) by 11 residues at the N terminus, and the degree of identity between the 2 isozymes is 70% with an alignment of 500 amino acid residues. Northern blot analysis demonstrated that the ALDH6 gene is expressed at low levels in many tissues and at higher levels in salivary gland, stomach, and kidney.
Hsu et al. (1994) determined that the ALDH6 gene spans about 37 kb and contains 13 exons. Putative TATA and CCAAT boxes and Sp1 binding sites were found in the 5-prime upstream region of the gene.
Hsu et al. (1994) mapped the ALDH6 gene to chromosome 15q26 by fluorescence in situ hybridization.
By in situ hybridization of chick and mouse embryos, Grun et al. (2000) demonstrated expression of Aldh1a3 in the developing sensory neuroepithelia of the eye, nose, and ear, and in discrete sites within the central nervous system. Expression of chick Aldh1a3 in a human choriocarcinoma cell line conferred increased sensitivity to retinol in a retinoic acid receptor (see 180240)-dependent reporter assay.
In affected individuals from 3 unrelated consanguineous families with bilateral severe microphthalmia (MCOP8: 615113), Fares-Taie et al. (2013) identified homozygous mutations in the ALDH1A3 gene (600463.0001-600463.0003).
In 2 Egyptian brothers and an unrelated Hispanic girl with isolated anophthalmia/microphthalmia, Yahyavi et al. (2013) identified homozygosity for nonsense mutations in the ALDH1A3 gene, K190X (600463.0004) and K389X (600463.0005). Yahyavi et al. (2013) generated Aldh1a3-knockdown zebrafish, which displayed a significant reduction in eye size. This phenotype could be rescued by wildtype ALDH1A3 mRNA, but not by mRNA containing the K190X or K389X mutations, indicative of likely loss of function caused by the mutations.
In zebrafish larvae injected with antisense morpholinos (MOs) against Aldh1a3, Yahyavi et al. (2013) observed a significant reduction in eye size at 48 to 72 hours postfertilization compared to wildtype larvae. Additional phenotypes seen with variable penetrance in morphants included delayed closure of the optic fissure, coloboma-like lesions, cardiac edema, and kinking of the tail. Confocal imaging at 5 days postfertilization showed that the tectum from wildtype larvae was filled with retinal axons and the optic tract had branched into stereotyped fascicles, whereas the tectum from MO-treated larvae appeared less innervated. The morphant phenotype was rescued by wildtype human ALDH1A3 mRNA.
In 3 affected individuals from a large, multiply consanguineous Pakistani family with bilateral severe microphthalmia (MCOP8; 615113), Fares-Taie et al. (2013) identified homozygosity for a 265C-T transition in the ALDH1A3 gene, resulting in an arg89-to-cys (R89C) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in 200 control chromosomes, SNP databases, or the Exome Variant Server. Transfection studies in HEK293 cells showed no significant difference in expression between the R89C mutant and wildtype ALDH1A3, although immunoblot analysis showed that the mutant protein was strongly reduced compared to wildtype, suggesting that the R89C mutant might be unstable and subject to degradation. In addition to their eye findings, the proband and her cousin were diagnosed with autism and 'possible autism,' respectively, and the cousin also had pulmonary stenosis and an atrial septal defect; Fares-Taie et al. (2013) suggested that these features might not be related to the mutation in ALDH1A3.
In an affected girl from a consanguineous Turkish family with bilateral severe microphthalmia (MCOP8; 615113), Fares-Taie et al. (2013) identified homozygosity for a 1477G-C transversion in the ALDH1A3 gene, resulting in an ala493-to-pro (A493P) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in 200 control chromosomes, SNP databases, or the Exome Variant Server. Transfection studies in HEK293 cells showed no significant difference in expression between the A493P mutant and wildtype ALDH1A3, although immunoblot analysis showed that the mutant protein was strongly reduced compared to wildtype, suggesting that the A493P mutant might be unstable and subject to degradation.
In an affected girl from a consanguineous Moroccan family with bilateral severe microphthalmia (MCOP8; 615113), Fares-Taie et al. (2013) identified homozygosity for a 475+1G-T splice site transversion in the ALDH1A3 gene, predicted to abolish a splice donor site and cause in-frame skipping of exon 5. Her unaffected parents and an unaffected brother were heterozygous for the mutation.
In 2 Egyptian brothers, 1 with bilateral anophthalmia and the other with right anophthalmia and left microphthalmia, posterior coloboma, and detached retina (MCOP8; 615113), Yahyavi et al. (2013) identified homozygosity for a 568A-G transition in the ALDH1A3 gene, resulting in a lys190-to-ter (K190X) substitution. The mutation was not found in the unaffected parents, in 92 Egyptian control chromosomes, or in 384 European chromosomes. Aldh1a3-knockdown zebrafish had significantly reduced eye size; the phenotype could be rescued by wildtype ALDH1A3 mRNA but not by mRNA containing the K190X mutation, indicative of likely loss of function.
In a 4.5-year-old Hispanic girl with bilateral anophthalmia and hypoplasia of the optic nerves and chiasm (MCOP8; 615113), Yahyavi et al. (2013) identified homozygosity for a 1165A-T transversion in the ALDH1A3 gene, resulting in a lys389-to-ter (K389X) substitution. The mutation was not found in her unaffected parents or in 120 ethnically diverse chromosomes. Aldh1a3-knockdown zebrafish had significantly reduced eye size; the phenotype could be rescued by wildtype ALDH1A3 mRNA, but not by mRNA containing the K389X mutation, indicative of likely loss of function.
Fares-Taie, L., Gerber, S., Chassaing, N., Clayton-Smith, J., Hanein, S., Silva, E., Serey, M., Serre, V., Gerard, X., Baumann, C., Plessis, G., Demeer, B., 9 others. ALDH1A3 mutations cause recessive anophthalmia and microphthalmia. Am. J. Hum. Genet. 92: 265-270, 2013. [PubMed: 23312594] [Full Text: https://doi.org/10.1016/j.ajhg.2012.12.003]
Grun, F., Hirose, Y., Kawauchi, S., Ogura, T., Umesono, K. Aldehyde dehydrogenase 6, a cytosolic retinaldehyde dehydrogenase prominently expressed in sensory neuroepithelia during development. J. Biol. Chem. 275: 41210-41218, 2000. [PubMed: 11013254] [Full Text: https://doi.org/10.1074/jbc.M007376200]
Hsu, L. C., Chang, W.-C., Hiraoka, L., Hsieh, C.-L. Molecular cloning, genomic organization, and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6. Genomics 24: 333-341, 1994. [PubMed: 7698756] [Full Text: https://doi.org/10.1006/geno.1994.1624]
Yahyavi, M., Abouzeid, H., Gawdat, G., de Preux, A.-S., Xiao, T., Bardakjian, T., Schneider, A., Choi, A., Jorgenson, E., Baier, H., El Sada, M., Schorderet, D. F., Slavotinek, A. M. ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm. Hum. Molec. Genet. 22: 3250-3258, 2013. [PubMed: 23591992] [Full Text: https://doi.org/10.1093/hmg/ddt179]