Low‐GGT intrahepatic cholestasis associated with biallelic USP53 variants: Clinical, histological and ultrastructural characterization

• DOI: 10.1111/liv.14422
• Publication Date: 2020-03-03T07:12:34Z
• Authors: Jing Zhang; Ye Yang; Jing‐Yu Gong; Li‐Ting Li; Jia‐Qi Li; Mei‐Hong Zhang; Yi Lu; Xin‐Bao Xie; Yu‐Ren Hong; Zhang Yu; A. S. Knisely; Jian‐She Wang
• Keywords: 0303 health sciences; 03 medical and health sciences; Cholestasis; Mutation; Hepatocytes; Humans; Infant; Cholestasis, Intrahepatic; Ubiquitin-Specific Proteases; gamma-Glutamyltransferase; Child; 3. Good health

Abstract Background & Aims In about 20% of children with cholestasis and normal or low serum gamma‐glutamyltransferase (GGT) activity, no aetiology is identified. We sought new genes implicated in paediatric hepatobiliary disease. Methods conducted whole‐exome sequencing 69 evaluated at our centre from 2011 to 2018 who had low‐GGT whom homozygous/compound heterozygous predictedly pathogenic variants (PPVs) ATP8B1 , ABCB11 NR1H4 MYO5B TJP2 were not found. Clinical records findings on light microscopy transmission electron liver biopsy materials reviewed. Results seven patients unrelated families, biallelic PPVs (10 total) found USP53 recently associated intrahepatic cholestasis. Seven classified as pathogenic: one canonical splicing, c.569 + 2T > C, six nonsense frameshifting: c.169C T (p.Arg57Ter), c.581delA (p.Arg195GlufsTer38), c.831_832insAG (p.Val279GlufsTer16), c.1012C (p.Arg338Ter), c.1426C (p.Arg476Ter) c.1558C (p.Arg520Ter). Three likely c.297G (p.Arg99Ser), c.395A G (p.His132Arg) c.878G (p.Gly293Val). all patients, jaundice began age <7 months. Cholestasis was transient, documented resolution hyperbilirubinaemia (oldest patient now aged 5 years) except one, lost follow‐up. Light identified intralobular cholestasis, giant‐cell change hepatocytes perisinusoidal‐perihepatocytic portal‐tract fibrosis. Ultrastructural study revealed elongated hepatocyte‐hepatocyte tight junctions. One deaf. Conclusion interacts the junction constituent TJP2. mutation can cause junctions, well deafness. Our extend a preliminary report disease indicate that may generate partial phenocopy