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Kotlarz, Daniel; Marquardt, Benjamin; Baroy, Tuva; Lee, Way S.; Konnikova, Liza; Hollizeck, Sebastian; Magg, Thomas; Lehle, Anna S.; Walz, Christoph; Borggraefe, Ingo; Hauck, Fabian; Bufler, Philip; Conca, Raffaele; Wall, Sarah M.; Schumacher, Eva M.; Misceo, Doriana; Frengen, Eirik; Bentsen, Beint S.; Uhlig, Holm H.; Hopfner, Karl-Peter; Muise, Aleixo M.; Snapper, Scott B.; Stromme, Petter; Klein, Christoph (2018): Human TGF-beta 1 deficiency causes severe inflammatory bowel disease and encephalopathy. In: Nature Genetics, Vol. 50, No. 3: pp. 344-348
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Abstract

Transforming growth factor (TGF)-beta 1 (encoded by TGFB1) is the prototypic member of the TGF-beta 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-beta 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-beta 1-LAP complex, which is suggestive of perturbed bioavailability of TGF-beta 1. Our study shows that TGF-beta 1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.