Two new USP53 gene mutations cause mild PFIC in Russian boy
Case report: Symptoms not extreme despite severe genetic deletion
Two new mutations in the USP53 gene were identified as the cause of a milder form of progressive familial intrahepatic cholestasis (PFIC), which resembled benign recurrent intrahepatic cholestasis (BRIC), in a Russian boy, a study showed.
“Despite carrying a gross deletion in USP53, our patient exhibited a BRIC-like [clinical profile] with intermittent cholestasis and preserved liver function, supporting the notion that USP53-related disease spans a clinical spectrum, and even disruptive variants may present with mild courses,” researchers wrote.
The study, “Case Report: Mild BRIC-like cholestasis despite a gross USP53 deletion — novel findings and literature review,” was published in Frontiers in Genetics.
Mutations in USP53 gene associated with PFIC type 7
Cholestasis is a condition marked by the slowed or stalled flow of bile, a digestive fluid produced in the liver and transported to the intestines through specific tubes, known as the bile ducts.
The condition causes bile to build up in the liver and leak into the bloodstream, leading to symptoms such as jaundice (yellowing of the skin and eyes) and pruritus (itching).
PFIC refers to a group of rare genetic diseases characterized by impaired bile production and/or secretion by liver cells, which causes intrahepatic cholestasis, or slowed bile flow within the liver, in early childhood.
There are several types of PFIC, each associated with mutations in a specific gene. Mutations in the USP53 gene have been associated with PFIC type 7. The USP53 gene provides instructions for producing an enzyme that helps neighboring cells adhere to each other. When this enzyme is missing or faulty, this adhesion is impaired, which in bile-producing liver cells results in intrahepatic cholestasis.
However, some studies have suggested that these mutations result in a relatively mild form, without progression to a stage where a liver transplant is necessary. Some of these milder forms are consistent with BRIC, “featuring episodic jaundice and pruritus with slow disease progression,” the researchers wrote.
Boy developed tissue scarring at a young age
In this report, a team of researchers in Russia described the case of a 16-year-old boy with BRIC-like disease that was found to be caused by two previously unreported mutations in the USP53 gene.
The boy had developed jaundice and pruritus at 5 months old, and blood tests showed very high bilirubin, a liver damage marker. A liver biopsy, where a small piece of tissue is removed for examination under a microscope, revealed tissue scarring (fibrosis) that showed progression to irreversible liver scarring, or cirrhosis, one year later.
At the age of 1 year, blood levels of certain liver enzymes were higher than normal, indicating liver damage, while levels of gamma-glutamyl transferase (GGT), another liver enzyme, were within the normal range. This pattern is typical of PFIC type 7.
From 1 to 14 years of age, the boy was monitored for signs of cholestasis and experienced only a temporary episode of high bilirubin at the age of 3 that resolved spontaneously.
At age 14, after a respiratory viral infection, he experienced several cholestasis symptoms, including jaundice, pruritus, pale stools, and dark urine. Blood tests showed high levels of bilirubin, bile acids, which are the main component of bile, and certain liver enzymes. His GGT remained normal.
Imaging scans showed an enlarged liver and spleen, inflammation of the bile ducts, and minor abnormalities in the kidney and gallbladder, a small organ where bile is stored. A new liver biopsy confirmed cirrhosis with signs of cholestasis.
Genetic testing revealed new mutation
Doctors ruled out other causes of liver disease, including viral and autoimmune hepatitis, and the boy was given ursodeoxycholic acid. The first-line treatment for cholestasis improves bile flow and is marketed in the U.S. under the brand names Actigall and Urso.
Treatment “resulted in clinical improvement, with normalization of liver function tests and a decrease in bilirubin levels,” the team wrote.
Genetic testing revealed a new mutation (c.1219A>T) in one of the USP53 gene copies that was inherited from his father and that resulted in the production of a shorter, nonworking enzyme.
In the other copy of the USP53 gene, inherited from the mother, the boy had the largest deletion in the USP53 gene reported to date, which removed the gene’s last portion.
These findings suggest that USP53-related disease may exist along a clinical spectrum, with [liver biopsy] features of PFIC but functional and clinical behavior resembling BRIC.
This deletion resulted in the production of an abnormal messenger RNA, the intermediate molecule derived from DNA that guides protein production, which was broken down early by a quality-control process called nonstop decay.
Together, the two USP53 mutations supported a diagnosis of PFIC type 7. However, even though both mutations were considered severe, the boy showed mild symptoms consistent with BRIC. Between episodes, his liver function returned to normal.
A review of 39 published cases of PFIC type 7 showed that “the majority exhibit a [profile] more typical of BRIC,” the researchers wrote. Despite advanced liver fibrosis, “the overall clinical course — marked by episodic cholestasis, long asymptomatic intervals, and preserved [liver] function — remains consistent with a BRIC-like [profile].”
“These findings suggest that USP53-related disease may exist along a clinical spectrum, with [liver biopsy] features of PFIC but functional and clinical behavior resembling BRIC,” the team wrote.
The data also support the inclusion of the USP53 gene in genetic panels for people showing cholestasis and low or normal GGT levels, the researchers concluded.
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