title: Sjögren-Larsson syndrome: seven novel mutations in the fatty aldehyde dehydrogenase gene ALDH3A2.
abstract: Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disease caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase (FALDH), an enzyme involved in lipid metabolism. We performed mutation analysis in probands or fetuses from 13 unrelated SLS families and identified seven novel ALDH3A2 mutations. Two mutations involved an insertion or deletion of a single guanine nucleotide at the same position in exon 9: c.1223delG and c.1223_1224insG. A 66-bp duplication in exon 2 probably arose from unequal crossing over within a mispaired 10-bp sequence that is normally repeated within the exon. Based on RT-PCR of fibroblast RNA, the c.1107+2T>G donor splice-site mutation in intron 7 produced two mRNA transcripts, one skipping exon 7 and the other skipping exons 6-8. Expression of the c.1139G>A mutation in exon 8, which is predicted to cause an amino acid substitution (Ser380Asn) in an evolutionarily conserved region of the FALDH catalytic domain, resulted in a protein with profoundly reduced enzymatic activity. By analyzing single nucleotide polymorphisms within the ALDH3A2 gene, we detected four different haplotypes among the new mutant alleles. These results demonstrate a rich diversity of mutations and haplotype associations in SLS.
authors.affiliation: Department of Pediatrics and Munroe-Meyer Institute, University of Nebraska Medical Center and Hobart Wiltse Center for the Study of Metabolic Disorders, Children's Hospital of Omaha, Omaha, Nebraska.
authors.forename: Gael
authors.initials: G
authors.lastname: Carney
authors.forename: Shu
authors.initials: S
authors.lastname: Wei
authors.forename: William B
authors.initials: WB
authors.lastname: Rizzo
mesh_terms: D000293:Adolescent; D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D004252:DNA Mutational Analysis / Q000379:methods; D005333:Fetus / Q000737:chemistry / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D009154:Mutation / Q000235:genetics*; D016111:Sjogren-Larsson Syndrome / Q000235:genetics*
chemical_list: D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase