2. Academic Validation
  3. RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities

RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities

  • Am J Hum Genet. 2019 Jul 3;105(1):108-121. doi: 10.1016/j.ajhg.2019.05.011.
Margot A Cousin 1,  Erin Conboy 2,  Jian-She Wang 3,  Dominic Lenz 4,  Tanya L Schwab 5,  Monique Williams 6,  Roshini S Abraham 7,  Sarah Barnett 8,  Mounif El-Youssef 9,  Rondell P Graham 8,  Luz Helena Gutierrez Sanchez 9,  Linda Hasadsri 8,  Georg F Hoffmann 4,  Nathan C Hull 10,  Robert Kopajtich 11,  Reka Kovacs-Nagy 11,  Jia-Qi Li 12,  Daniela Marx-Berger 13,  Valérie McLin 14,  Mark A McNiven 15,  Taofic Mounajjed 8,  Holger Prokisch 11,  Daisy Rymen 16,  Ryan J Schulze 15,  Christian Staufner 4,  Ye Yang 12,  Karl J Clark 5,  Brendan C Lanpher 17,  Eric W Klee 18
Affiliations

Affiliations

  • 1 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
  • 2 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 3 Department of Pediatrics, Jinshan Hospital, Fudan University, 201508 Shanghai, China; Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 201102 Shanghai, China.
  • 4 Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
  • 5 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • 6 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • 7 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.
  • 8 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • 9 Department of Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
  • 10 Department of Radiology, Division of Pediatric Radiology, Mayo Clinic, Rochester, MN 55905, USA.
  • 11 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 12 Department of Pediatrics, Jinshan Hospital, Fudan University, 201508 Shanghai, China.
  • 13 Pediatric Nephrology, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland.
  • 14 Pediatric Gastroenterology Unit, University Hospitals Geneva, Rue Willy-Donzé 6, 1211 Geneva, Switzerland.
  • 15 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.
  • 16 Department of Metabolic Diseases, University Children's Hospital Zurich, Zurich, Switzerland.
  • 17 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected].
  • 18 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected].
PMID: 31204009 DOI: 10.1016/j.ajhg.2019.05.011
Abstract

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/Infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or Infection, Golgi-to-ER transport is suppressed and Autophagy is promoted through UVRAG regulation by mTOR. Aberrant Autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.

Keywords

RINT1; autophagy; autosomal recessive; disorder of intracellular trafficking; recurrent acute liver failure; skeletal anomalies.

Figures