Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy

Nat Genet. 2018 Mar;50(3):344-348. doi: 10.1038/s41588-018-0063-6.

Daniel Kotlarz ^# ¹, Benjamin Marquardt ^# ¹, Tuva Barøy ² ³, Way S Lee ⁴, Liza Konnikova ⁵ ⁶ ⁷, Sebastian Hollizeck ¹, Thomas Magg ¹, Anna S Lehle ¹, Christoph Walz ⁸, Ingo Borggraefe ¹, Fabian Hauck ¹, Philip Bufler ¹, Raffaele Conca ¹, Sarah M Wall ⁵, Eva M Schumacher ⁹, Doriana Misceo ² ³, Eirik Frengen ² ³, Beint S Bentsen ⁹ ¹⁰, Holm H Uhlig ¹¹, Karl-Peter Hopfner ¹², Aleixo M Muise ¹³ ¹⁴ ¹⁵, Scott B Snapper ⁵ ⁶ ¹⁶, Petter Strømme ³ ⁹, Christoph Klein ¹⁷

Affiliations

1 Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, Germany.
2 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
3 Faculty of Medicine, University of Oslo, Oslo, Norway.
4 Department of Pediatrics, University Malaya Medical Center, Kuala Lumpur, Malaysia.
5 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
6 Harvard Medical School, Boston, MA, USA.
7 Department of Pediatric and Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.
8 Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany.
9 Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
10 Department of Pediatric Research, Pediatric Liver Kidney Alimentary Nutrition and Transplantation Research Group, Oslo University Hospital, Oslo, Norway.
11 Translational Gastroenterology Unit and Department of Pediatrics, University of Oxford, Oxford, UK.
12 Department of Biochemistry and Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
13 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
14 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
15 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
16 Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
17 Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, Germany. christoph.klein@med.uni-muenchen.de.
# Contributed equally.

PMID: 29483653 DOI: 10.1038/s41588-018-0063-6

Abstract

Transforming growth factor (TGF)-β1 (encoded by TGFB1) is the prototypic member of the TGF-β family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis^1,2. Following its discovery ³ , enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties^4,5, pro- and anti-inflammatory effects ⁶ , or pro- and anti-fibrinogenic characteristics ⁷ . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-β1-LAP complex, which is suggestive of perturbed bioavailability of TGF-β1. Our study shows that TGF-β1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

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