ClinVar

In an 11-year-old boy (patient 1), born of unrelated parents from Malaysia, with inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE; 618213), Kotlarz et al. (2018) identified compound heterozygous missense mutations in the TGFB1 gene: a c.328C-T transition (c.328C-T, ENST00000221930.5), resulting in an arg110-to-cys (R110C) substitution in the latency-associated peptide (LAP) domain, and a c.1159T-C transition, resulting in a cys387-to-arg (C387R; 190180.0009) substitution in the mature growth factor domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Molecular modeling predicted that the R110C mutation could alter the interaction between 2 functional elements of the protein and that the C387R mutation could affect folding or stability of the TGFB1 growth factor domain. In vitro functional expression studies in HEK293 cells showed that the R110C mutation resulted in reduced levels of secreted TGFB1 and reduced downstream signaling compared to controls. Cells transfected with the C387R mutation had no detectable secreted TGFB1 and no downstream signaling activity, consistent with a loss of function. Colonic biopsy from the patient showed reduced levels of phosphorylated SMAD2 (601366)/SMAD3 (603109) in lamina propria mononuclear cells. Reduced levels of phosphorylated SMAD2/3 were also seen in mononuclear cells from an unrelated patient with Crohn disease, suggesting a common pathophysiology.