title: 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.
authors: INSERM U781 & Department of Genetics, Paris Descartes University, Paris, France.
authors: Lucas
authors: L
authors: Fares-Taie
authors: Sylvie
authors: S
authors: Gerber
authors: Nicolas
authors: N
authors: Chassaing
authors: Jill
authors: J
authors: Clayton-Smith
authors: Sylvain
authors: S
authors: Hanein
authors: Eduardo
authors: E
authors: Silva
authors: Margaux
authors: M
authors: Serey
authors: Valérie
authors: V
authors: Serre
authors: Xavier
authors: X
authors: Gérard
authors: Clarisse
authors: C
authors: Baumann
authors: Ghislaine
authors: G
authors: Plessis
authors: Bénédicte
authors: B
authors: Demeer
authors: Lionel
authors: L
authors: Brétillon
authors: Christine
authors: C
authors: Bole
authors: Patrick
authors: P
authors: Nitschke
authors: Arnold
authors: A
authors: Munnich
authors: Stanislas
authors: S
authors: Lyonnet
authors: Patrick
authors: P
authors: Calvas
authors: Josseline
authors: J
authors: Kaplan
authors: Nicola
authors: N
authors: Ragge
authors: Jean-Michel
authors: JM
authors: Rozet
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000445:Aldehyde Oxidoreductases; D000853:Anophthalmos / Q000201:enzymology* / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D008040:Genetic Linkage; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008850:Microphthalmos / Q000201:enzymology* / Q000235:genetics*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D050505:Mutant Proteins; D000445:Aldehyde Oxidoreductases; D000444:Aldehyde Dehydrogenase; C018699:aldehyde dehydrogenase (NAD(P)+)