ALDH1A3 mutations cause recessive anophthalmia and microphthalmia

Abstract

Purpose: Anophthalmia and microphthalmia (A/M) are early eye development anomalies resulting in absent or small ocular globes, respectively. A/Ms occur as syndromic or nonsyndromic forms. They are genetically heterogenous with some mutations in some genes responsible for both anophthalmia and microphthalmia. The purpose of this study was to identify the disease gene involved in A/M in a large inbreed Pakistani Family and other unrelated A/M families.

Methods: A combination of homozygosity mapping, exome sequencing and Sanger sequencing, was used to identify the disease mutation in the Pakistani family and to screen the ALDH1A3 gene for mutations in additional unrelated A/M patients.

Results: We identified homozygosity for a missense mutation in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in the Pakistani family. The screening of the gene is a cohort of A/M patients excluding known A/M genes allowed identifying two additional homozygote ALDH1A3 mutations including another missense change and a splice-site mutation in two consanguineous families. The review of the clinical files of patients showed that patients with ALDH1A3 mutations had A/M with occasional orbital cystic, neurological and cardiac anomalies.

Conclusions: ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during the early eye development. Transitory expression of mutant ALDH1A3 cDNAs showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. While the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic acid synthesis dysfunction and early eye development in human.

Keywords: 539 genetics • 638 pathology: human • 497 development