title: Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia.
abstract: OBJECTIVE
  This study aimed to identify the underlying genetic defect responsible for anophthalmia/microphthalmia.
  
  
  METHODS
  In total, two Turkish families with a total of nine affected individuals were included in the study. Affymetrix 250 K single nucleotide polymorphism genotyping and homozygosity mapping were used to identify the localisation of the genetic defect in question. Coding region of the ALDH1A3 gene was screened via direct sequencing. cDNA samples were generated from primary fibroblast cell cultures for expression analysis. Reverse transcriptase PCR (RT-PCR) analysis was performed using direct sequencing of the obtained fragments.
  
  
  RESULTS
  The causative genetic defect was mapped to chromosome 15q26.3. A homozygous G>A substitution (c.666G>A) at the last nucleotide of exon 6 in the ALDH1A3 gene was identified in the first family. Further cDNA sequencing of ALDH1A3 showed that the c.666G>A mutation caused skipping of exon 6, which predicted in-frame loss of 43 amino acids (p.Trp180_Glu222del). A novel missense c.1398C>A mutation in exon 12 of ALDH1A3 that causes the substitution of a conserved asparagine by lysine at amino acid position 466 (p.Asn466Lys) was observed in the second family. No extraocular findings-except for nevus flammeus in one affected individual and a variant of Dandy-Walker malformation in another affected individual-were observed. Autistic-like behaviour and mental retardation were observed in three cases.
  
  
  CONCLUSIONS
  In conclusion, novel ALDH1A3 mutations identified in the present study confirm the pivotal role of ALDH1A3 in human eye development. Autistic features, previously reported as an associated finding, were considered to be the result of social deprivation and inadequate parenting during early infancy in the presented families.
authors.affiliation: Department of Medical Genetics, School of Medicine, Pamukkale University, Denizli, Turkey.
authors.forename: C Nur
authors.initials: CN
authors.lastname: Semerci
authors.affiliation: Department of Medical Biology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey.
authors.forename: Ersan
authors.initials: E
authors.lastname: Kalay
authors.affiliation: Department of Ophthalmology, School of Medicine, Pamukkale University, Denizli, Turkey.
authors.forename: Cem
authors.initials: C
authors.lastname: Yıldırım
authors.affiliation: Department of Medical Biology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey.
authors.forename: Tuba
authors.initials: T
authors.lastname: Dinçer
authors.affiliation: Department of Pediatric Neurology, Denizli State Hospital of Ministry of Health, Denizli, Turkey.
authors.forename: Akgün
authors.initials: A
authors.lastname: Olmez
authors.affiliation: Department of Medical Biology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey.
authors.forename: Bayram
authors.initials: B
authors.lastname: Toraman
authors.affiliation: Department of Radiology, School of Medicine, Pamukkale University, Denizli, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Koçyiğit
authors.affiliation: Department of Ophthalmology, State Hospital, Şuhut-Afyonkarahisar, Afyon, Turkey.
authors.forename: Yunus
authors.initials: Y
authors.lastname: Bulgu
authors.affiliation: Department of Medical Genetics, School of Medicine, Pamukkale University, Denizli, Turkey.
authors.forename: Volkan
authors.initials: V
authors.lastname: Okur
authors.affiliation: Department of Medical Genetics, School of Medicine, Pamukkale University, Denizli, Turkey.
authors.forename: Lale
authors.initials: L
authors.lastname: Satıroğlu-Tufan
authors.affiliation: Department of Medical Genetics, Gene Mapping Laboratory, School of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Nurten A
authors.initials: NA
authors.lastname: Akarsu
mesh_terms: D000293:Adolescent; D000445:Aldehyde Oxidoreductases / Q000235:genetics*; D000853:Anophthalmos / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D022821:RNA Splice Sites; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)