Genetic and biochemical study of dual hereditary jaundice: Dubin-Johnson and Gilbert's syndromes. Haplotyping and founder effect of deletion in ABCC2.
Dual hereditary jaundice, a combination of Dubin-Johnson and Gilbert's syndromes, is a rare clinical entity resulting from the compound defects of bilirubin conjugation and transport. We aimed to study the hereditary jaundice in 56 members from seven seemingly unrelated Roma families, to find the causal genetic defect and to estimate its origin in Roma population. On the basis of biochemical results of total and conjugated serum bilirubin and clinical observations, ABCC2 gene, TATA box and phenobarbital enhancer (PBREM) of UGT1A1 gene were analyzed by sequencing, RFLP and fragment analysis. We found a novel variant c.1013_1014delTG in the eighth exon of ABCC2 gene in 17 individuals in homozygous state. Dual defect NG_011798.1:c.[1013_1014delTG]; NG_002601.2:g.[175492_175493insTA] in homozygous state was found in four subjects. Biochemical analyses of porphyrins and coproporphyrin isomers in urine performed by HPLC showed inverted ratio of excreted coproporphyrin, with the predominance of coproporphyrin I (up to 100%), typical for patients with Dubin-Johnson syndrome. Pursuant cultural and social specifics of the population led us to suspect a founder effect; therefore, we performed a haplotype study using genotyping data from Affymetrix Genome-Wide Human SNP Array 6.0. As a result, we detected a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families, and estimated the age of the ancestral variant to 178-185 years. In this study, we found a novel deletion in ABCC2 gene, described genetic and biochemical features of dual hereditary jaundice and confirmed the existence of founder effect and common haplotype among seven Roma families.
Department of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
Lenka
L
Slachtova
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
Ondrej
O
Seda
Department of Pediatrics, P. J. Safarik University, Kosice, Vienna, Slovakia.|Institute of Medical Genetics, University of Vienna, Vienna, Austria.
Jana
J
Behunova
Department of Medical Genetics, Alpha Medical, Spisska Nova Ves, Slovakia.
Martin
M
Mistrik
Department of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
Pavel
P
Martasek
D001663:Bilirubin / Q000378:metabolism; D003306:Coproporphyrins / Q000652:urine; D005260:Female; D018703:Founder Effect; D017353:Gene Deletion; D005878:Gilbert Disease / Q000175:diagnosis / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007566:Jaundice, Chronic Idiopathic / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D016385:TATA Box; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D003306:Coproporphyrins; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human