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Sjögren‐Larsson syndrome: Seven novel mutations in the fatty aldehyde dehydrogenase gene ALDH3A2
Author(s) -
Carney Gael,
Wei Shu,
Rizzo William B.
Publication year - 2004
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9262
Subject(s) - exon , biology , genetics , intron , mutation , gene , tandem exon duplication , exon skipping , microbiology and biotechnology , haplotype , compound heterozygosity , splice site mutation , rna splicing , exon trapping , alternative splicing , allele , rna
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. © 2004 Wiley‐Liss, Inc.