PMID- 10577908
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20200824
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 65
IP  - 6
DP  - 1999 Dec
TI  - The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty
      aldehyde dehydrogenase gene.
PG  - 1547-60
AB  - Sjogren-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.
FAU - Rizzo, W B
AU  - Rizzo WB
AD  - Departments of Pediatrics and Human Genetics, Medical College of Virginia,
      Virginia Commonwealth University, Richmond, VA 23298, USA. wrizzo@hsc.vcu.edu.
FAU - Carney, G
AU  - Carney G
FAU - Lin, Z
AU  - Lin Z
LA  - eng
GR  - M01 RR000065/RR/NCRR NIH HHS/United States
GR  - R01 AR044552/AR/NIAMS NIH HHS/United States
GR  - AR44552/AR/NIAMS NIH HHS/United States
GR  - RR00065/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (Codon, Terminator)
RN  - 0 (RNA, Messenger)
RN  - EC 1.2.- (Aldehyde Oxidoreductases)
RN  - EC 1.2.1.48 (long-chain-aldehyde dehydrogenase)
SB  - IM
MH  - Aldehyde Oxidoreductases/*genetics/metabolism
MH  - Alleles
MH  - Alternative Splicing/genetics
MH  - Base Sequence
MH  - Catalysis
MH  - Cell Line
MH  - Codon, Terminator/genetics
MH  - Exons/genetics
MH  - Family Health
MH  - Gene Frequency/genetics
MH  - Genes, Recessive/genetics
MH  - Genetic Variation/genetics
MH  - Haplotypes/genetics
MH  - Humans
MH  - Introns/genetics
MH  - Mutation/*genetics
MH  - Polymorphism, Genetic/genetics
MH  - RNA Stability/genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - Sjogren-Larsson Syndrome/*enzymology/*genetics
PMC - PMC1288365
EDAT- 1999/12/01 09:00
MHDA- 2000/03/21 09:00
CRDT- 1999/12/01 09:00
PHST- 1999/12/01 09:00 [pubmed]
PHST- 2000/03/21 09:00 [medline]
PHST- 1999/12/01 09:00 [entrez]
AID - S0002-9297(07)63574-5 [pii]
AID - 10.1086/302681 [doi]
PST - ppublish
SO  - Am J Hum Genet. 1999 Dec;65(6):1547-60. doi: 10.1086/302681.