Clinical and genetic characterization of Chanarin-Dorfman syndrome patients: first report of large deletions in the ABHD5 gene.
BACKGROUND
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive disorder characterized by nonbullous congenital ichthyosiform erythroderma (NCIE) and an intracellular accumulation of triacylglycerol (TG) droplets in most tissues. The clinical phenotype involves multiple organs and systems, including liver, eyes, ears, skeletal muscle and central nervous system (CNS). Mutations in ABHD5/CGI58 gene are associated with CDS.


METHODS
Eight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5' regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs.


RESULTS
Five different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A) and two large deletions (c.898_*320del and c.662-1330_773+46del). All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described.


CONCLUSIONS
These results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.
Department of Psychology, Catholic University of the Sacred Heart, Milan, Italy.
Chiara
C
Redaelli
Rosalind A
RA
Coleman
Laura
L
Moro
Catherine
C
Dacou-Voutetakis
Solaf Mohamed
SM
Elsayed
Daniele
D
Prati
Agostino
A
Colli
Donatella
D
Mela
Roberto
R
Colombo
Daniela
D
Tavian
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics / Q000503:physiopathology; D017490:Ichthyosis, Lamellar / Q000235:genetics / Q000503:physiopathology; D007223:Infant; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009135:Muscular Diseases / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013577:Syndrome
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human