title: First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype.
abstract: Microphthalmia, anophthalmia, and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used single nucleotide polymorphism (SNP) homozygosity mapping (HM) and targeted next-generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous microanophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double-nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, including one individual with Matthew-Wood syndrome (MWS; MCOPS9). STRA6 encodes a transmembrane receptor involved in vitamin A uptake, a process essential to eye development and growth. We have shown that the G304K mutant STRA6 protein is mislocalized and has severely reduced vitamin A uptake activity. Furthermore, we reproduced the MCOPCB phenotype in a zebrafish disease model by inhibiting retinoic acid (RA) synthesis, suggesting that diminished RA levels account for the eye malformations in STRA6 p.G304K patients. The current study demonstrates that STRA6 mutations can cause isolated eye malformations in addition to the congenital anomalies observed in MWS.
authors: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
authors: Jillian
authors: J
authors: Casey
authors: Riki
authors: R
authors: Kawaguchi
authors: Maria
authors: M
authors: Morrissey
authors: Hui
authors: H
authors: Sun
authors: Paul
authors: P
authors: McGettigan
authors: Jens E
authors: JE
authors: Nielsen
authors: Judith
authors: J
authors: Conroy
authors: Regina
authors: R
authors: Regan
authors: Elaine
authors: E
authors: Kenny
authors: Paul
authors: P
authors: Cormican
authors: Derek W
authors: DW
authors: Morris
authors: Peter
authors: P
authors: Tormey
authors: Muireann Ní
authors: MN
authors: Chróinín
authors: Breandan N
authors: BN
authors: Kennedy
authors: SallyAnn
authors: S
authors: Lynch
authors: Andrew
authors: A
authors: Green
authors: Sean
authors: S
authors: Ennis
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000853:Anophthalmos / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods; D003103:Coloboma / Q000235:genetics* / Q000469:parasitology; D003241:Consanguinity; D005190:Family; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007494:Ireland; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008850:Microphthalmos / Q000235:genetics* / Q000469:parasitology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D015027:Zebrafish
chemical_list: D008565:Membrane Proteins; C519685:STRA6 protein, human