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. 1999 Dec;65(6):1547-60.
doi: 10.1086/302681.

The Molecular Basis of Sjögren-Larsson Syndrome: Mutation Analysis of the Fatty Aldehyde Dehydrogenase Gene

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The Molecular Basis of Sjögren-Larsson Syndrome: Mutation Analysis of the Fatty Aldehyde Dehydrogenase Gene

W B Rizzo et al. Am J Hum Genet. .
Free PMC article


Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). To define the molecular defects causing SLS, we performed mutation analysis of the FALDH gene in probands from 63 kindreds with SLS. Among these patients, 49 different mutations-including 10 deletions, 2 insertions, 22 amino acid substitutions, 3 nonsense mutations, 9 splice-site defects, and 3 complex mutations-were found. All of the patients with SLS were found to carry mutations. Nineteen of the missense mutations resulted in a severe reduction of FALDH enzyme catalytic activity when expressed in mammalian cells, but one mutation (798G-->C [K266N]) seemed to have a greater effect on mRNA stability. The splice-site mutations led to exon skipping or utilization of cryptic acceptor-splice sites. Thirty-seven mutations were private, and 12 mutations were seen in two or more probands of European or Middle Eastern descent. Four single-nucleotide polymorphisms (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 with multiple SNP haplotypes, suggesting that these mutations originated independently on more than one occasion or were ancient SLS genes that had undergone intragenic recombination. Our results demonstrate that SLS is caused by a strikingly heterogeneous group of mutations in the FALDH gene and provide a framework for understanding the genetic basis of SLS and the development of DNA-based diagnostic tests.


Figure  1
Figure 1
Large deletion mutation (153+5→386–408del+ins19bp) in a homozygous SLS patient. A, PCR amplification of a fragment of the FALDH gene spanning exons 1–3 in a normal control patient, in the mother of the patient, and in the homozygous SLS patient (SLS). MW = molecular-weight markers. The normal PCR product is 3.5 kb, whereas the product of the deletion mutation is 0.7 kb. B, Illustration of the normal and deleted FALDH gene. C, DNA sequences at the deletion breakpoints. A duplicated portion of intron 2 has been inserted and is underlined with a dotted line. Nucleotides flanking the deletion/insertion are numbered according to the FALDH cDNA nomenclature.
Figure  2
Figure 2
Aberrant splicing caused by three splice-donor mutations at the junction of exon 5 and intron 5. A, Normal and mutant DNA sequences. Exon sequence is indicated by uppercase letters, intron sequence by lowercase letters. B, Amplification of fibroblast FALDH mRNA by RT-PCR shows that all three mutations result in two abnormal transcripts, one of which skips exon 5 and the other of which skips exons 4 and 5.
Figure  3
Figure 3
Splice-acceptor–site mutation 681–14T→A and its effect on FALDH mRNA and protein. A, RT-PCR products, obtained with the use of primers in exons 4 and 5, separated in a 10% polyacrylamide gel. The left lane shows normal RNA, and the right lane shows patient RNA demonstrating an abnormal larger product arising from a 24-bp insertion in the patient's mRNA. B, Mutation and sequence of the abnormally spliced larger transcript. The larger product was amplified from an aberrant FALDH transcript that arose from utilization of a cryptic splice-acceptor site upstream of the mutation, whereas the smaller product represents the normally spliced transcript. Normal and cryptic splice-acceptor sites are underlined. The mutation is denoted by a boxed letter “a.”
Figure  4
Figure 4
Location of mutations within the FALDH cDNA. The major FALDH cDNA containing exons 1–10 is shown. Exon 9′, which is spliced between exons 9 and 10 in a minor FALDH transcript, contains no mutations and is not illustrated. Arrows indicate mutation locations. The numbers above some arrows refer to the number of different mutations located within several base pairs at the same location. An asterisk (*) above an arrow indicates the beginning of the large deletion mutation encompassing intron 1 and extending through exon 2 and most of intron 2. All splice-site mutations alter intron sequences.

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