ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

Abstract

Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although 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 anomalies in humans.

A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred

“…Here, we report on yet another ALDH1A3 missense mutation, namely, p.Val71Met that causes A/M. Although the role of retinoic-acid signaling in the eye development is well established, the results provided by Fares-Taie et al 14 and that of ours ascertain the genetic linkage between retinoic-acid synthesis dysfunction and an early eye development anomalies, namely, A/M, in humans.…”

“…Methionine (Met) is a rather rare amino acid in proteins, moderately hydrophobic, that similar to Val tends to stabilize a-helices. Unlike residues 89 and 493, reported by Fares-Taie et al, 14 Val71 is not involved in subunit-subunit interactions.…”

“…The families reported by Fares-Taie et al 14 have inconsistently demonstrated additional features (autism and heart anomalies), which may be mutation related or incidental. Fares-Taie et al 14 question the validity of these additional signs.…”

“…ALDH1A3 is a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development. 3,6,7 Fares-Taie et al 14 have recently shown that mutations in ALDH1A3 cause A/M. Two missense mutations and one splice mutation, namely, p.Arg89Cys, p.Ala493Pro and c.475 þ 1G-4T, were reported to segregate in three consanguineous families with A/M.…”

Genes relacionados con microftalmia y anoftalmia hereditarias

“…El gen ALDH1A3 se encuentra ubicado en el cromosoma 15q26.3 y recientemente se ha demostrado que sus mutaciones son causa de microftalmia y anoftalmia de herencia autosómica recesiva 44,45 .…”