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

Am J Hum Genet. 2015 Jul 2;97(1):163-9. doi: 10.1016/j.ajhg.2015.05.009.

Tobias B Haack ¹, Christian Staufner ², Marlies G Köpke ¹, Beate K Straub ³, Stefan Kölker ², Christian Thiel ², Peter Freisinger ⁴, Ivo Baric ⁵, Patrick J McKiernan ⁶, Nicola Dikow ⁷, Inga Harting ⁸, Flemming Beisse ⁹, Peter Burgard ², Urania Kotzaeridou ², Joachim Kühr ¹⁰, Urban Himbert ¹¹, Robert W Taylor ¹², Felix Distelmaier ¹³, Jerry Vockley ¹⁴, Lina Ghaloul-Gonzalez ¹⁴, Johannes Zschocke ¹⁵, Laura S Kremer ¹⁶, Elisabeth Graf ¹⁶, Thomas Schwarzmayr ¹⁶, Daniel M Bader ¹⁷, Julien Gagneur ¹⁷, Thomas Wieland ¹⁶, Caterina Terrile ¹⁶, Tim M Strom ¹, Thomas Meitinger ¹, Georg F Hoffmann ², Holger Prokisch ¹⁸

Affiliations

1 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
2 Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
3 Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
4 Children's Hospital Reutlingen, 72764 Reutlingen, Germany.
5 Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, 10000 Zagreb, Croatia.
6 Liver Unit, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
7 Institute of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
8 Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
9 Ophthalmology Department, University Hospital Heidelberg, 69120 Heidelberg, Germany.
10 Children's Hospital Karlsruhe, 76133 Karlsruhe, Germany.
11 Children's Hospital St. Elisabeth, 56564 Neuwied, Germany.
12 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
13 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
14 University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
15 Division of Human Genetics, Innsbruck Medical University, 6020 Innsbruck, Austria.
16 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
17 Computational Genomics, Gene Center, Ludwig Maximilians University, 81377 Munich, Germany.
18 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address: [email protected].

PMID: 26073778 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.

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