U.S. Department of Health and Human Services

Biliary Atresia Susceptibility Gene Identified in Patients

​Scientists participating in NIDDK’s Childhood Liver Disease Research and Education Network (ChiLDREN) have utilized patient samples and an animal model to identify a genetic deletion that may play a role in the development of biliary atresia. Biliary atresia (BA) is a life-threatening condition affecting newborn infants in which the bile ducts—tubes that carry bile from the liver to the gallbladder for storage and to the small intestine to aid fat digestion—become blocked and destroyed, leading to a back-up of bile and liver damage. Most infants with biliary atresia require surgery to survive and may later need a liver transplant as well. Although its causes are unknown, some have speculated that it results from a combination of environmental and genetic factors. A group of researchers at a site participating in the NIDDK’s ChiLDREN Network aimed to build on past indings of an association between a region of the genome and BA by looking for a speciic gene(s) within this region that confers increased disease risk. By comparing genetic sequences from patient blood samples at the Network site with healthy controls, they zeroed in on a small part of this genetic region that was deleted in the patients. In healthy individuals, this region contains only one gene, called GPC1, coding for a protein involved in organ development. To more directly observe the functional impact of this gene’s deletion on biliary development, they turned to an animal model with an analogous form of the gene (gpc1) and similar biliary anatomy—the zebraish. In this model, the research group could use molecular inhibitors to reduce activity of the ish’s gpc1 gene early in development, mimicking the deletion of this gene in the patients with BA. They observed defects in biliary anatomy in the ish larvae with reduced gpc1, but not in the control larvae. Applying this knowledge to the human disease, they looked for the GPC1 protein in liver samples from patients with BA and healthy controls. The livers of patients with BA showed lower levels of GPC1 compared to the livers from healthy controls. This study identiies GPC1 as a new potential susceptibility gene that may be lacking in patients with BA and shows the mechanism in an animal model by which this gene deletion may result in human disease. The ChiLDREN Network has enabled studies of BA such as this one through collecting samples from a suficient number of patients affected by this relatively rare disease.

Cui S, Leyva-Vega M, Tsai EA, et al. Evidence from human
and zebraish that GPC1 is a biliary atresia susceptibility
gene. Gastroenterology 144: 1107-1115, 2013.