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


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 homeostasis1,2. Following its discovery3, enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects6, or pro- and anti-fibrinogenic characteristics7. 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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Fig. 1: Identification of a biallelic TGFB1 mutation in patient 1 with very early-onset inflammatory bowel disease and global neurological defects.
Fig. 2: Effects of TGFB1 mutations on the biosynthesis and bioavailability of TGF-β1.


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We are very grateful to our patients and their parents for allowing us to study their diseases. We thank the medical staff at the Dr. von Hauner Children’s Hospital, Oslo University Hospital and University Malaya Medical Center. In particular, we would like to acknowledge pathologist D. Klotz (Oslo University Hospital) for the histology of colonic biopsies. Whole-exome sequencing of family A was conducted at the Next-Generation Sequencing facility at the Dr. von Hauner Children’s Hospital under the supervision of M. Rohlfs. The sequencing service of family B was provided by the Norwegian Sequencing Centre, a national technology platform supported by the Functional Genomics and Infrastructure Programs of the Research Council of Norway and the Southeastern Regional Health Authorities, and the sequencing data of family B were analyzed by A. Holmgren. We acknowledge the assistance of the Flow Cytometry Core Facility at the Dr. von Hauner Children’s Hospital and of the Harvard Medical School CyTOF Core. Samples from the patient with CED were provided with support of the Oxford Gastrointestinal Illness Biobank and Biomedical Research Center Oxford. We gratefully acknowledge our bioinformatician, J. Puchalka, who died in a tragic accident during the course of the investigations. This work has been supported by The Leona M. and Harry B. Helmsley Charitable Trust, the Collaborative Research Consortium SFB1054 (DFG), PID-NET (BMBF), BioSysNet, the European Research Council, the Gottfried–Wilhelm–Leibniz Program (DFG), the DAAD network on ‘Rare Diseases and Personalized Therapies’, the German Center for Infection Research (DZIF) and the Care-for-Rare Foundation. W.S.L. was partly funded by University Malaya High Impact Research (UM.C/625/HIR/MOHE/CHAN/13/1). D.K. has been a scholar funded by the Else Kröner-Fresenius-Stiftung, the Daimler und Benz Stiftung and the Reinhard Frank-Stiftung.

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Authors and Affiliations



D.K. and C.K. designed and directed the study, managed recruitment of study participants, obtained clinical samples, supervised B.M. and interpreted the data; B.M. conducted and analyzed functional assays on heterologous cellular models; D.M., E.F. and P.S. supervised T.B. and E.M.S., initiated genetic analysis and drafted the clinical report of P2 and P3, and provided critical revision of the manuscript; T.B. acquired and interpreted genetic data from P2 and P3; R.C. conducted immunophenotypic analysis of PBMCs; T.M. and A.S.L. performed functional immunological assays; S.M.W. performed CyTOF analysis; L.K. supervised S.M.W. and analyzed the CyTOF results; S.H. performed the bioinformatics analysis of sequencing data; K.-P.H. conducted structural analysis of protein variants encoded by the identified TGFB1 mutations; W.S.L., I.B., F.H., P.B., E.M.S. and B.S.B. cared for the patients, collected patient samples and drafted clinical reports; C.W. examined histology; H.H.U. provided clinical information and a specimen from a patient with CED; A.M.M. and S.B.S. screened local cohorts of patients with very early-onset inflammatory bowel disease for mutations in TGFB1 and were instrumental in the interpretation of the human data; C.K. provided laboratory resources; and D.K. and C.K. wrote the manuscript with help from B.M. The manuscript was reviewed and approved by all co-authors.

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Correspondence to Christoph Klein.

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Integrated supplementary information

Supplementary Figure 1 CD103 expression in lamina propria T cells from patient 1.

CyTOF analysis of CD103 expression in colonic lamina propria mononuclear cells derived from patients without IBD (controls: uninflamed; inflamed), a patient with Crohn’s disease and P1. The percentage of CD103-expressing cells is shown for CD3+CD4+ (top), CD3+CD8+ (middle) and CD127lo/–CD25+ (bottom) T cells.

Supplementary Figure 2 Sanger sequencing of patient 1.

Chromatograms of DNA Sanger sequencing identifying a compound heterozygous mutation in TGBF1 that segregates with the disease phenotype in P1.

Supplementary Figure 3 Clinical phenotype and mutational analysis of TGF-β1 deficiency in patients 2 and 3.

a, Pedigree of consanguineous Pakistani family B with two affected children. b, Sanger sequencing results confirming segregation of the identified biallelic TGFB1 missense mutation with the disease phenotype in pedigree B. c, Gastrointestinal findings in P3. Colonoscopy (top) revealed extensive colitis, and histology on colonic biopsies (bottom) showed chronic active inflammation accompanied by abscesses and crypt branching. d, Cerebral MRI images of P3 at the age of 2 years displaying gross cortical atrophy with widening of the subarachnoid spaces, delayed myelination and marked thinning of the corpus callosum.

Supplementary Figure 4 Normal STAT6 activity in lamina propria immune cells from patient 1.

CyTOF analysis of STAT6 phosphorylation (Tyr641; p-STAT6) in lamina propria mononuclear cells derived from patients without IBD (controls: uninflamed, blue; inflamed, orange), a patient with Crohn’s disease (CD) (green) and P1 (black). Histogram plots show baseline p-STAT6 in live cells that were gated on the indicated populations (left), and the heat map representation depicts the corresponding median expression values (MEV) for p-STAT6.

Supplementary Figure 5 Gating strategy for FACS analysis.

Gating strategy used in Fig. 1d.

Supplementary Figure 6 Gating strategy for CyTOF analysis.

a,b, Gating strategies used in Supplementary Fig. 1 (a) and in Fig. 2h and Supplementary Fig. 3 (b).

Supplementary Figure 7 Uncropped immunoblots.

Uncropped original immunoblots of Fig. 2d. The cropped areas are marked in red. Molecular weight markers are indicated in kDa.

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Supplementary Figures 1–7 and Supplementary Tables 1–4

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Kotlarz, D., Marquardt, B., Barøy, T. et al. Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat Genet 50, 344–348 (2018).

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