Document Detail

Cosegregation of intragenic markers with a novel mutation that causes Crigler-Najjar syndrome type I: implication in carrier detection and prenatal diagnosis.
MedLine Citation:
PMID:  8102509     Owner:  NLM     Status:  MEDLINE    
Crigler-Najjar syndrome type 1 (CN-1) is a familial disorder characterized by severe unconjugated hyperbilirubinemia and jaundice and leads to kernicterus, neurological damage, and eventual death unless treated with liver transplantation. Previous reports identified mutations in the UGT1 gene complex to be the cause of the disease. The total absence of all phenol/bilirubin UGT proteins and their activities in liver homogenate of a CN-1 patient was determined by enzymological and immunochemical analysis. A novel homozygous nonsense mutation (CGA-->TGA) was identified in the patient by the combined techniques of PCR and direct sequencing. This mutation was located in exon 3 of the constant region in the gene complex which is common to all phenol and bilirubin UGTs. The segregation of the mutation in the patient's family was analyzed and confirmed the recessive nature of the disease. Newly developed intragenic polymorphic probes (UGT1* 4 and UGT-Const) were used on Southern blots of MspI-digested genomic DNA of the patient and his family. The segregation of individual alleles within the family was observed from haplotypes generated. Comparison of the segregation of haplotypes with the mutation for the patient and his family revealed the allele identified by the A1-B1-C2 haplotype to be carrying the mutation. The risk of recombination occurring is negligible, because of the intragenic nature of the probes. This study demonstrates the potential usefulness of these probes in carrier detection and prenatal/presymptomatic diagnosis.
N Moghrabi; D J Clarke; B Burchell; M Boxer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of human genetics     Volume:  53     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  1993 Sep 
Date Detail:
Created Date:  1993-09-16     Completed Date:  1993-09-16     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  722-9     Citation Subset:  IM    
Department of Pathology, University of Dundee, Ninewells Hospital and Medical School, Scotland.
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MeSH Terms
Base Sequence
Bilirubin / metabolism
Blotting, Southern
Chromosomes, Human, Pair 2
Crigler-Najjar Syndrome / diagnosis*,  enzymology,  genetics*
DNA Mutational Analysis
DNA Probes / diagnostic use
Genes, Recessive
Genetic Markers
Glucuronosyltransferase / deficiency,  genetics*
Heterozygote Detection
Isoenzymes / genetics
Linkage (Genetics)
Liver / enzymology
Molecular Sequence Data
Multigene Family
Phenols / metabolism
Polymorphism, Restriction Fragment Length
Prenatal Diagnosis
Propofol / contraindications
Grant Support
//Wellcome Trust
Reg. No./Substance:
0/DNA Probes; 0/Genetic Markers; 0/Isoenzymes; 0/Phenols; 2078-54-8/Propofol; 635-65-4/Bilirubin; EC

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