https://www.ncbi.nlm.nih.gov/pubmed/32124521 Cholestasis

Liver Int. 2020 Mar 2. doi: 10.1111/liv.14422. [Epub ahead of print]

Low-GGT intrahepatic cholestasis associated with biallelic USP53 variants: clinical, histological, and ultrastructural characterization.

Zhang J1,2, Yang Y1,2, Gong JY1, Li LT2, Li JQ1, Zhang MH1, Lu Y2, Xie XB2, Hong YR3, Zhang YU3, Knisely AS4, Wang JS2.

Abstract

BACKGROUND AND AIMS:
In about 20% of children with cholestasis and normal or low serum gamma-glutamyltransferase (GGT) activity, no etiology is identified. We sought new genes implicated in pediatric hepatobiliary disease.

METHODS:
We conducted whole exome sequencing in 69 children evaluated at our center from 2011 to 2018 who had low-GGT cholestasis and in whom homozygous / compound heterozygous predictedly pathogenic variants (PPV) in ATP8B1, ABCB11, NR1H4, MYO5B, or TJP2 were not found. Clinical records and findings on light microscopy and transmission electron microscopy of liver-biopsy materials were reviewed.

RESULTS:
In 7 patients from 7 unrelated families, biallelic PPV (10 in total) were found in USP53, recently associated with intrahepatic cholestasis. Seven variants were classified as pathogenic: one canonical splicing, c.569+2T>C, and six nonsense or frameshifting: c.169C>T (p.Arg57Ter), c.581delA (p.Arg195GlufsTer38), c.831_832insAG (p.Val279GlufsTer16), c.1012C>T (p.Arg338Ter), c.1426C>T (p.Arg476Ter), and c.1558C>T (p.Arg520Ter). Three were likely pathogenic: c.297G>T (p.Arg99Ser), c.395A>G (p.His132Arg), and c.878G>T (p.Gly293Val). In all patients, jaundice began at age <7mo. Cholestasis was transient, with documented resolution of hyperbilirubinemia in all (oldest patient now aged 5y) except one, who was lost to follow-up. Light microscopy identified intralobular cholestasis, giant-cell change of hepatocytes, and perisinusoidal-perihepatocytic and portal-tract fibrosis. Ultrastructural study revealed elongated hepatocyte-hepatocyte tight junctions. One patient was deaf.

CONCLUSION:
USP53 interacts with the tight-junction constituent TJP2. TJP2 mutation can cause low-GGT intrahepatic cholestasis, with elongated hepatocyte-hepatocyte tight junctions, as well as deafness. Our findings extend a preliminary report of USP53 disease and indicate that USP53 mutation may generate a partial phenocopy of TJP2 disease. (250 words).