Mutations in CGI-58, the Gene Encoding a New Protein of the Esterase/Lipase/Thioesterase Subfamily, in Chanarin-Dorfman Syndrome

Abstract

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.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…Diseases that are classically regarded as ichthyosis in the previously published scientific literature and that will continue to be included are shown in Figs 4 and 5. They include Sjögren-Larsson syndrome 75,76 ( Fig 5, B), Refsum syndrome, 77,78 neutral lipid storage disease with ichthyosis (also referred to as ChanarinDorfman syndrome) (Fig 5, G), 40,79,80 ichthyosis folliculariseatrichiaephotophobia syndrome (Fig 5, D), 81,82 Conradi-Hünermann-Happle syndrome (CDPX2) (Fig 5, F ), 83,84 multiple sulfatase deficiency, 85,86 congenital reticular ichthyosiform erythroderma also referred to as ichthyosis variegata 87 (or ichthyosis en confettis 88 ) (Fig 4, E ), and ichthyosis prematurity syndrome 89,90 (Fig 5, E ). In ichthyosis prematurity syndrome, affected pregnancies exhibit abnormal amniotic fluid both on ultrasound imaging and clinically.…”

Perilipin A Mediates the Reversible Binding of CGI-58 to Lipid Droplets in 3T3-L1 Adipocytes

“…The name CGI-58 derives from a Comparative Gene Identification initiative that annotated 150 novel transcripts conserved between Caenorhabditis elegans and humans (22). CGI-58 is a member of the esterase, thioesterase, and lipase subfamily of ␣/␤-hydrolase fold enzymes (23). The protein sequence includes a highly conserved active site that, in most ␣/␤-hydrolases, includes a nucleophilic serine residue known to be important in catalysis.…”

“…Interestingly, the CGI-58 sequence encodes an asparagine in place of this catalytic serine (23). Significantly, eight different mutations in CGI-58 were recently identified as causative factors in Chanarin-Dorfman Syndrome (23), a neutral lipid storage disorder (NLSD) characterized by ichthyosis, hepatic steatosis and hepatomegaly, developmental defects, and the accumulation of triacylglycerol-containing lipid droplets in leukocytes, basal keratinocytes, hepatocytes, myocytes, and other cells (23)(24)(25). The eight mutations known to lead to NLSD include truncations, null alleles, and three distinct point mutations.…”

Expecting the most unexpected – a harlequin baby! A case report and literature analysis

“…Autosomal recessive congenital ichthyosis -Lipoxygenase-3 and 12R-lipoxygenase defect [16]. Dorfman -Chanarin syndrome -CGI-58 defect [17]. Tangier disease -Defect in cholesterol transport between liver and other tissues [2][3][4][5].…”