ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

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• 作者：Lucas Fares-Taie¹ ; ¹⁵ ; Sylvie Gerber¹ ; ¹⁵ ; Nicolas Chassaing² ; ³ ; ¹⁵ ; Jill Clayton-Smith⁴ ; Sylvain Hanein¹ ; Eduardo Silva⁵ ; Margaux Serey¹ ; Valé ; rie Serre¹ ; ⁶ ; Xavier Gé ; rard¹ ; Clarisse Baumann⁷ ; Ghislaine Plessis⁸ ; Bé ; né ; dicte Demeer⁹ ; Lionel Bré ; tillon¹⁰ ; Christine Bole¹¹ ; Patrick Nitschke¹² ; Arnold Munnich¹ ; Stanislas Lyonnet¹ ; Patrick Calvas² ; ³ ; Josseline Kaplan¹ ; ^{josseline.kaplan@inserm.fr} ; Nicola Ragge¹³ ; ¹⁴ ; Jean-Michel Rozet¹ ; ^{jean-michel.rozet@inserm.fr}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：7 February, 2013
• 年：2013
• 卷：92
• 期：2
• 页码：265-270
• 全文大小：315 K

文摘

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.