New PLEC gene mutations are likely cause of girls’ liver ailment PFIC
Cases follow earlier report in Taiwan of variants linked to liver condition
Scientists in Thailand have identified four new mutations in the PLEC gene as the likely cause of progressive familial intrahepatic cholestasis (PFIC) in two unrelated baby girls.
The mutations may mark the third and fourth reported cases of PFIC potentially caused by PLEC mutations, after variants in the gene were associated with the liver disease in two siblings in Taiwan.
All four cases had signs of cholestasis, or slowed flow of the digestive fluid bile from the liver to the intestines, and jaundice, which is a yellowing of the skin and whites of the eyes. They also showed low levels of plectin, the protein coded by PLEC.
“Our study in two unrelated families further confirmed that PLEC could be related to cholestatic jaundice and provided evidence suggesting the role of plectin in cholestasis,” the researchers wrote.
The study, “Novel PLEC variants associated with infantile cholestasis,” was published in Clinical Genetics.
PFIC is a group of rare genetic liver diseases marked by symptoms that typically emerge in early childhood due to problems in liver cells’ production and/or release of bile. The defects are caused by inherited mutations in a number of genes, each linked to a different PFIC type.
These mutations lead to intrahepatic cholestasis, meaning bile flow is slowed within the liver. Cholestasis can cause bile to build up and damage the organ, which can lead to liver failure. Bile may also leak into blood, resulting in jaundice.
PLEC gene mutations and liver disease
In 2019, researchers reported on two siblings with PFIC caused by two different mutations in PLEC, a gene that provides instructions for producing the protein plectin that helps maintain tissue integrity in many organs. While PLEC mutations have been associated with conditions that mostly affect the skin and muscle, this was the first time such mutations were linked to a liver disease.
Here, researchers in Thailand described two unrelated baby girls who carry four new PLEC mutations that were likely the cause of their PFIC-like clinical profile.
The first girl displayed signs of cholestasis, including jaundice, when she was 2 months old. Blood tests showed she had abnormally high levels of gamma-glutamyl transpeptidase (GGT), a marker of liver or bile duct disease, and of other markers of liver problems.
The girl developed cirrhosis, or irreversible liver scarring, at 9 months and received a liver transplant from her mother three months later. At her last follow-up when she was about 2.5, she was in good condition and had normal liver function.
The second girl developed jaundice when she was 1 week old, and had signs of cholestasis and liver damage, but low blood GGT levels. At 6 months, the jaundice persisted and her liver function mildly declined. The girl ultimately developed sepsis, an extreme immune system response to an infection that leads to tissue damage, organ failure, and death if it isn’t treated promptly. She died of liver failure at 9 months.
After excluding other causes of liver disease, genetic analyses revealed PLEC mutations in both girls.
The first girl inherited the c.71-11768C>T mutation from her father and the c.4331G>T mutation from her mother. The second girl inherited the c.592C>T mutation from her father and the c.4322G>A mutation from her mother. None were previously described and were classified as likely disease-causing. The mutations are also rare within the general population.
Plectin’s role in the liver
Liver biopsies showed signs of cholestasis, low plectin, and proteins involved in bile acid release from liver cells, and signs of structural abnormalities in liver cells.
The researchers hypothesized that there is a critical role for plectin in the structural integrity of the liver, which was disrupted in the girls due to the PLEC mutations. Neither girl, nor the two siblings previously reported to have PLEC-associated PFIC, exhibited skin or muscle-related symptoms.
“It is possible that other symptoms of [plectin] deficiency could emerge later in life,” and therefore “long-term follow-up of patients with PLEC-related cholestasis is essential,” the researchers wrote. “Alternatively, the identified variants could result in a milder or tissue-specific form of [plectin] deficiency, affecting only the liver and biliary system while sparing other tissues and systems typically supported by plectin.”
The researchers acknowledged their study was limited by its small sample.
“Further experiments and the identification of additional patients from other families are still needed to clarify the [disease-causing] role of PLEC [mutations] in relation to cholestasis,” they wrote.
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