Study: New ABCB4 mutations tied to different ages of PFIC3 onset
Combined data show same mutation in both copies leads to disease at younger age
Two cases of progressive familial intrahepatic cholestasis type 3 (PFIC3) with markedly different ages of disease onset due to new mutations in the ABCB4 gene were reported in a recent study.
When the study’s researchers combined data from these and other published PFIC3 cases, they found that patients who carry the same mutation in both ABCB4 gene copies, each inherited from one parent, develop the disease at a significantly younger age.
“These insights lay a foundation for early diagnosis, optimal treatment selection, and further research into PFIC3,” the researchers wrote.
The study, “Identification of novel ABCB4 variants and genotype-phenotype correlation in progressive familial intrahepatic cholestasis type 3,” was published in Nature Scientific Reports.
PFIC is a group of rare genetic liver diseases marked by impaired bile production and/or secretion from liver cells. Bile is a digestive fluid made in the liver and transported to the intestines via a series of tubes called bile ducts. A hallmark feature of the disease is intrahepatic cholestasis, when bile flow slows or stalls in the bile ducts in the liver, resulting in it building up to toxic levels and causing damage that can progress to irreversible liver scarring (cirrhosis) and organ failure.
Common symptoms include jaundice, or the yellowing of the skin and whites of the eyes, dark urine, and itchy skin.
PFIC type 3 is caused by mutations in the ABCB4 gene that disrupt the production or function of MDR3, an enzyme that helps neutralize bile components to prevent damage to bile duct cells.
“Different types of variants … and different variant sites have been found to have different effects on the function of the MDR3 protein, and can independently influence clinical manifestations and disease progression,” wrote researchers in China who described the cases of two PFIC3 patients who carry three new ABCB4 mutations.
Different mutations
The first patient was a girl who developed jaundice at 16 months and the second was a boy who showed jaundice when he was 13 years old. Blood tests revealed elevated levels of several biomarkers of cholestasis in both.
Abdominal scans showed the girl had an enlarged liver and spleen, and several other signs of severe liver disease in the boy, including cirrhosis, fluid buildup in the belly, called ascites, and high blood pressure in the portal vein that runs through the liver, or portal hypertension.
Genetic testing showed each patient carried a different mutation in both ABCB4 gene copies. The girl inherited a known mutation, c.3136C>T, from her mother and a new mutation, c.904G>T, from her father. The c.3136C>T mutation is known to result in a shorter, likely nonworking, version of MDR3. c.904G>T is a missense mutation, meaning it leads to a change in an amino acid, a protein building block, in the resulting MDR3.
“The severe early onset in Patient 1 suggests significant impairment of MDR3 function,” the researchers wrote.
The boy inherited two previously unknown ABCB4 mutations: c.2493G>C from his mother and c.1230+1G>A from his father. c.2493G>C is a missense mutation, while c.1230+1G>A is a splicing mutation that can change the version of protein produced.
Computer analyses predicted that both new missense mutations changed the structure of the MDR3 protein, likely causing disease, and that the new splicing mutation was also likely disease-causing.
Despite treatment with standard medications, liver disease progressed in both patients and they underwent a liver transplant for liver failure, the girl at age 2 and the boy when he was 23. After the procedure, biomarkers of cholestasis and liver function normalized in both, and the girl continued to grow and develop normally.
Determining genetic, clinical associations
The researchers then combined data from the two patients and 118 other PFIC3 cases reported in the literature to evaluate potential associations between genetic and clinical profiles.
Most patients (62.7%) had different mutations in each ABCB4 copy (complex heterozygous mutations), while a little over a third (37.2%) carried the same mutation in both ABCB4 copies (homozygous mutations). Most (76.9%) of the 252 identified mutations were missense.
More than half the patients (58.45) developed the disease in infancy (birth to 4 years), 18.6% in childhood (ages 5-11), 14.4% during adolescence (ages 12-17), and 8.4% in adulthood.
Patients with homozygous mutations had a significantly younger mean age at onset than those with complex heterozygous mutations (2.67 vs. 8.78 years), suggesting the latter have a greater impact on MDR3 function. Sex had no impact on age of onset.
Lastly, a computer analysis indicated mutations in exons 7 and 10, two protein-coding regions of the ABCB4 gene that showed the highest mutation frequency, were significant predictors of age of onset, “highlighting the importance of targeting specific exon locations for early detection and intervention in clinical practice,” the researchers wrote.
“This study underscores the critical role of genetic analysis in diagnosing PFIC3 and highlights the significant impact of specific ABCB4 gene variants on disease onset and progression,” they wrote, adding the cases provide “valuable insights into the genetic underpinnings of PFIC3, emphasizing the importance of early detection and personalized treatment strategies.”
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