Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome.
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive form of nonbullous congenital ichthyosiform erythroderma (NCIE) that is characterized by the presence of intracellular lipid droplets in most tissues. We previously localized a gene for a subset of NCIE to chromosome 3 (designated "the NCIE2 locus"), in six families. Lipid droplets were found in five of these six families, suggesting a diagnosis of CDS. Four additional families selected on the basis of a confirmed diagnosis of CDS also showed linkage to the NCIE2 locus. Linkage-disequilibrium analysis of these families, all from the Mediterranean basin, allowed us to refine the NCIE2 locus to an approximately 1.3-Mb region. Candidate genes from the interval were screened, and eight distinct mutations in the recently identified CGI-58 gene were found in 13 patients from these nine families. The spectrum of gene variants included insertion, deletion, splice-site, and point mutations. The CGI-58 protein belongs to a large family of proteins characterized by an alpha/beta hydrolase fold. CGI-58 contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. Interestingly, CGI-58 differs from other members of the esterase/lipase/thioesterase subfamily in that its putative catalytic triad contains an asparagine in place of the usual serine residue.
Lefèvre
C
C
Centre National de Génotypage, 91057 Evry Cedex, France.
Jobard
F
F
Caux
F
F
Bouadjar
B
B
Karaduman
A
A
Heilig
R
R
Lakhdar
H
H
Wollenberg
A
A
Verret
J L
JL
Weissenbach
J
J
Ozgüc
M
M
Lathrop
M
M
Prud'homme
J F
JF
Fischer
J
J
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004950:Esterases / Q000737:chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008049:Lipase / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020161:Physical Chromosome Mapping; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013577:Syndrome
D009097:Multienzyme Complexes; D012333:RNA, Messenger; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; D004950:Esterases; D008049:Lipase