The molecular basis of Sjogren-Larsson syndrome: Mutation analysis of the fatty aldehyde dehydrogenase gene

Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder character ized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). To define the molecular defects ca using SLS, we performed mutation analysis of the FALDH gene in probands fro m 63 kindreds with SLS. Among these patients, 49 different mutations-includ ing 10 deletions, 2 insertions, 22 amino acid substitutions, 3 nonsense mut ations, 9 splice-site defects, and 3 complex mutations-were found. All of t he patients with SLS were found to carry mutations. Nineteen of the missens e mutations resulted in a severe reduction of FALDH enzyme catalytic activi ty when expressed in mammalian cells, but one mutation (798G-->C [K266N]) s eemed to have a greater effect on mRNA stability. The splice-site mutations led to exon skipping or utilization of cryptic acceptor-splice sites. Thir ty-seven mutations were private, and 12 mutations were seen in two or more probands of European or Middle Eastern descent. Four single-nucleotide poly morphisms (SNPs) were found in the FALDH gene. At least four of the common mutations (551C-->T, 682C-->T, 733G-->A, and 798+1delG) were associated wit h multiple SNP haplotypes, suggesting that these mutations originated indep endently on more than one occasion or were ancient SLS genes that had under gone intragenic recombination. Our results demonstrate that SLS is caused b y a strikingly heterogeneous group of mutations in the FALDH gene and provi de a framework for understanding the genetic basis of SLS and the developme nt of DNA-based diagnostic tests.