A new genetic study by The Children’s Hospital of Philadelphia researchers may shed light on the causes of the rare childhood disease biliary atresia. The leading cause of liver transplantation in children, biliary atresia (BA) is a rare, life-threatening condition in which the ducts that carry bile from the liver to the gallbladder become blocked.
Children’s Hospital’s Randy Matthews, MD, PhD, led this new collaborative genetic study of BA, a condition occurring exclusively in neonatal livers. A relatively rare disease, BA affects approximately one out of every 15,000 infants, and is more common in Asians and African Americans. If left untreated, BA can lead to liver damage and cirrhosis of the liver, and patients with BA often require liver transplants.
With this study, Dr. Matthews and other CHOP researchers, including Marcella Devoto, PhD, and Nancy B. Spinner, PhD, hoped to better understand BA’s etiology, which, while still poorly understood, is “believed to involve exposure of a genetically susceptible individual to certain environmental factors.” Both Drs. Matthews and Spinner are members of Children’s Hospital’s Fred and Suzanne Biesecker Pediatric Liver Center.
The study — which was funded in part by the Center, as well as the NIH and the Childhood Liver Disease Research and Education Network, a network of clinicians and researchers working “to improve the lives of children and families dealing with rare liver diseases” — was published recently in Gastroenterology.
“Despite recent inroads into the understanding the mechanisms leading to fibroinflammatory damage to the biliary tree, uncovering the cause of BA continues to be a major challenge,” Dr. Matthews noted. Because BA is so rare, and because there have been few documented cases showing clear familial inheritance, studies into the condition’s possible genetic causes have been difficult, Dr. Matthews said.
After searching for copy number variations (CNVs) — losses or gains in DNA sequence — in patients with BA compared to healthy individuals, Dr. Spinner and her team identified a candidate gene, GPC1. Moving to an animal model, Dr. Matthews and his team then studied the effects of using morpholino antisense oligonucleotides to reduce expression of gpc1 in zebrafish.
Zebrafish, a type of tropical freshwater fish that is commonly used in a variety of scientific and medical studies, “offer a facile animal model for this type of ‘precision medicine’, as they are more amenable to rapid genetic manipulation than mice, and can be analyzed more quickly as well due to their rapid and ex utero development,” Dr. Matthews pointed out.
The researchers showed that disruption of gpc1 (as the gene is known in zebrafish) led to biliary defects in zebrafish. This finding, combined with the fact that the investigators also found “GPC1 abnormalities in all BA patient liver samples examined,” support “a potential role for GPC1 as a susceptibility gene for BA,” Dr. Matthews said.
“This is the first study to identify a potential BA risk gene in patients and demonstrate functional defects in the biliary system in model organism studies,” the study’s authors note.
This study builds on previous work by Dr. Spinner’s lab, which associated a region of chromosome 2 with BA. Studies of other possible BA-associated genes are currently underway in the Spinner lab, and Dr. Matthews noted that any future investigations into BA’s causes — and possible treatments — would make use of that work.
While “the ability to test infants for genetic susceptibility to BA is clearly far off,” future studies that shed light on biliary atresia’s pathogenesis could help “identify treatments that are more effective than the existing therapy,” Dr. Matthews said. That said, once tests for BA genetic susceptibility are developed, they will likely include testing for GPC1 defects, he added.