Rare Childhood Liver Disease Traced to Defective Lipid Metabolism Gene

In more technical terms, these individuals manifested a moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis.

To discover the mutation that linked these cases investigators at Schneider Children's Medical Center (Tel Aviv, Israel) and their colleagues at the University of Western Ontario (London, Canada) performed SNP (single-nucleotide polymorphism) array-based homozygosity mapping of DNA samples obtained from the patient group.

They reported in the January 2012 issue of the American Journal of Human Genetics that they had found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that were listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. OMIM is a comprehensive, authoritative, and timely compendium of human genes and genetic phenotypes maintained on the Internet by Johns Hopkins University (Baltimore, MD, USA). The full-text, referenced overviews in OMIM contain information on all known Mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype.

The investigators then performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in the GPD1gene, which encodes glycerol-3-phosphate dehydrogenase 1. Results revealed a homozygous splicing mutation, which resulted in an aberrantly spliced mRNA in the 10 affected individuals. This mutation predicted the synthesis of a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition.

Prevalence of the mutation in the village was thought to be due to a high marriage rate between first cousins. Introduction of genetic counseling could reduce the number of babies born with the defective gene.

Related Links:
Schneider Children's Medical Center
University of Western Ontario
Johns Hopkins University