Novel splice‐site mutation in ATP8B1 results in atypical Progressive Familial Intrahepatic Cholestasis Type 1. Issue 3 (26th February 2013)

• Record Type: Journal Article
• Authors: Copeland, Emily; Renault, Nisa; Renault, Marc; Dyack, Sarah; Bulman, Dennis E; Bedard, Karen; Otley, Anthony; Magee, Fergall; Acott, Philip; Greer, Wenda L
• Is Part Of: Journal of gastroenterology and hepatology. Volume 28:Issue 3(2013:Mar.)
• Page Start: 560
• Page End: 564
• Publication Date: 2013-02-26
• Subjects: Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; Liver -- Diseases -- Periodicals; Gastroenterology -- Periodicals; Liver Diseases -- Periodicals; 616.33
• DOI: 10.1111/j.1440-1746.2012.07290.x
• Languages: English
• ISSNs: 0815-9319

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jgh7290-sec-0001" sec-type="section"> <title>Background and Aim</title> <p>Our objective was to identify the molecular genetic basis of an Alagille‐like condition not linked to <italic>JAG1</italic> or <italic>NOTCH2</italic> in two related sibships.</p> </sec> <sec id="jgh7290-sec-0002" sec-type="section"> <title>Methods</title> <p>Because of common ancestry, and an autosomal recessive mode of inheritance, it was hypothesized that all affected and no unaffected individuals would be homozygous for the same haplotype in the region of the causative gene. Single nucleotide polymorphism arrays were therefore used to genotype 3 affected individuals from two sibships, their mothers and four unaffected siblings, to identify regions of homozygosity. Genes within the largest regions were prioritized and sequenced for mutations. Mutant RNA transcripts were also sequenced.</p> </sec> <sec id="jgh7290-sec-0003" sec-type="section"> <title>Results</title> <p>A novel splice acceptor site mutation in the <italic>ATP8B1</italic> gene was identified (a G–C preceding exon 16 resulting in a 4 bp deletion and frameshift from the 5′ end of exon 16). This result was unexpected because <italic>ATP8B1</italic> mutations are associated with Progressive Familial Intrahepatic Cholestasis Type 1 (PFIC1). Intrahepatic bile duct paucity, cardiac anomalies, renal tubular acidosis and hypothyroidism led to an initial diagnosis of Alagille Syndrome. However, in retrospect, abnormal sweat chloride, normal gamma‐glutamyl transferase, normal to low cholesterol, and an autosomal recessive mode of inheritance were consistent with PFIC1. Renal tubular acidosis, hypothyroidism and cardiac anomalies have not previously been associated with PFIC1.</p> </sec> <sec id="jgh7290-sec-0004" sec-type="section"> <title>Conclusion</title> <p>This work expands the phenotypic spectrum of PFIC1, and highlights the overlap in clinical phenotype between Alagille Syndrome and PFIC1. Knowledge of the causative mutation allows for carrier testing and prenatal diagnosis in this community.</p> </sec> </abstract>