title: ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm.
abstract: The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems.
authors.affiliation: Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143-0748, USA.
authors.forename: Mani
authors.initials: M
authors.lastname: Yahyavi
authors.forename: Hana
authors.initials: H
authors.lastname: Abouzeid
authors.forename: Ghada
authors.initials: G
authors.lastname: Gawdat
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: de Preux
authors.forename: Tong
authors.initials: T
authors.lastname: Xiao
authors.forename: Tanya
authors.initials: T
authors.lastname: Bardakjian
authors.forename: Adele
authors.initials: A
authors.lastname: Schneider
authors.forename: Alex
authors.initials: A
authors.lastname: Choi
authors.forename: Eric
authors.initials: E
authors.lastname: Jorgenson
authors.forename: Herwig
authors.initials: H
authors.lastname: Baier
authors.forename: Mohamad
authors.initials: M
authors.lastname: El Sada
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000853:Anophthalmos / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D059472:Exome; D005123:Eye / Q000254:growth & development / Q000473:pathology; D005260:Female; D016678:Genome; D006720:Homozygote; D006801:Humans; D007223:Infant; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008297:Male; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism; D009897:Optic Chiasm / Q000002:abnormalities*; D009900:Optic Nerve / Q000002:abnormalities*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)