Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy

Tobias B Haack ,Thomas Wieland,Caterina Terrile,Flemming Beisse,Holger Prokisch,Elisabeth Graf,Urban Himbert,Julien Gagneur,Peter Freisinger,Christian Staufner,Thomas Schwarzmayr,Urania Kotzaeridou,Christian Thiel,Inga Harting,Jerry Vockley,Thomas Meitinger,Nicola Dikow,Johannes Zschocke,Felix Distelmaier,Peter Burgard,Stefan Kölker,Daniel M Bader ,Laura S Kremer ,Ivo Barić ,Lina Ghaloul‐Gonzalez ,Georg F Hoffmann ,Marlies Köpke ,Robert W Taylor ,Tim M Strom ,J Kühr ,Beate K Straub ,Patrick Mckiernan

doi:10.1016/j.ajhg.2015.05.009

Abstract

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. Immunoblot analysis of mutant fibroblasts showed reduced protein levels of NBAS and its proposed interaction partner p31, both involved in retrograde transport between endoplasmic reticulum and Golgi. We recommend NBAS analysis in individuals with acute infantile liver failure, especially if triggered by fever.

Highlights

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency
We report the identification of homozygous or compound heterozygous mutations in NBAS in 11 individuals with recurrent acute liver failure (RALF) starting in infancy
We subsequently studied 15 additional unrelated individuals with unresolved RALF and ALF from four additional clinical centers by Sanger sequencing

Summary

Introduction

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Known causes of recurrent acute liver failure (RALF) with clinical and biochemical hepatic recovery in the interval include fulminant viral hepatitis, autoimmune hepatitis, disorders of long-chain fatty acid oxidation and the carnitine cycle, dihydrolipoamide dehydrogenase (E3) deficiency (MIM: 246900), and Wolcott-Rallison syndrome (MIM: 226980).[3,4,5,6,7] Here we report the identification of homozygous or compound heterozygous mutations in NBAS (neuroblastoma amplified sequence) in 11 individuals with RALF starting in infancy.

Results

Conclusion