ORPHA: 250923;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p13 | ?Aniridia 3 | 617142 | Autosomal dominant | 3 | TRIM44 | 612298 |
A number sign (#) is used with this entry because of evidence that aniridia-3 (AN3) is caused by heterozygous mutation in the TRIM44 gene (612298) on chromosome 11p13. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of aniridia, see AN1 (106210).
Zhang et al. (2015) studied a 4-generation Chinese family in which 8 patients had aniridia without systemic abnormalities. The patients ranged in age from 7 to 55 years, and all had complete bilateral defects of the iris. Visual acuity gradually decreased over time due to the irregular lens opacity caused by lack of iris block and direct exposure to the sun. Visual impairment was exacerbated by associated complications, including cataract and glaucoma. Cataract was observed in patients over the age of 10 years. None of the patients exhibited congenital corneal opacity.
In 7 affected and 13 unaffected members of a 4-generation Chinese family segregating autosomal dominant aniridia, Zhang et al. (2015) performed linkage and haplotype analysis and identified a shared haplotype in the 7 patients at chromosome 11p13, with a maximum lod score of 2.72 at D11S907 (theta = 0).
In a 4-generation Chinese family with aniridia mapping to chromosome 11p13, negative for mutation in the coding and splicing regions of the PAX6 (607108), FOXC1 (601090), and PITX2 (601542) genes, Zhang et al. (2015) performed whole-exome sequencing and identified 4 patient-specific mutations: 2 variants in the 3-prime UTR of PAX6, and 2 missense mutations in the TRIM44 gene (612298), located approximately 4 Mb from PAX6. Functional analysis indicated that the 2 PAX6 variants were unlikely to contribute to the pathogenesis of aniridia in this pedigree. However, the identified TRIM44 G155R substitution (612298.0001), which is located at a conserved residue and was not found in public variant databases, showed significantly stronger suppression of PAX6 expression than wildtype. The other TRIM44 variant involved a nonconserved residue, was found in Asian and European populations of the ExAC database, and exhibited suppression of PAX6 at a similar level as wildtype TRIM44. Zhang et al. (2015) concluded that TRIM44 is a negative regulator that restricts expression of PAX6 and that the G155R mutation significantly enhances its activity, representing a novel pathogenic mechanism for aniridia.
Zhang, X., Qin, G., Chen, G., Li, T., Gao, L., Huang, L., Zhang, Y., Ouyang, K., Wang, Y., Pang, Y., Zeng, B., Yu, L. Variants in TRIM44 cause aniridia by impairing PAX6 expression. Hum. Mutat. 36: 1164-1167, 2015. [PubMed: 26394807] [Full Text: https://doi.org/10.1002/humu.22907]