BACKGROUND Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue, Ttc7, result in a multisystemic disease, mostly affecting the epithelial barriers and immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE We sought to identify whether TTC7A mutations dysregulate epithelial cells only or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations. METHODS Ttc7-mutated (Ttc7) mice were crossed to generate double-mutant (Rag2Ttc7) and triple-mutant (Rag2IL2rgTtc7) mice. These models, together with bone marrow chimeras, were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of the Ttc7 mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7 fibroblasts. RESULTS We observed that the severity of epithelial hyperproliferation was accentuated by lymphocytes, whereas the phenotype was not induced by transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. Ttc7-mutated mouse fibroblasts expressed increased transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3γ (Reg3γ). In a xenograft model Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. CONCLUSION Our results reveal a previously unsuspected fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies.