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Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in  TMEM38B  was identified.  TMEM38B  encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP 3 R-mediated Ca 2+  release from intracellular stores. The molecular mechanisms by which  TMEM38B  mutations cause OI are unknown. We identified 3 probands with recessive defects in  TMEM38B . TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced  TMEM38B  transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca 2+ , associated with deficient store-operated calcium entry, although SERCA and IP 3 R have normal stability. Notably, steady state ER Ca 2+  is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca 2+  flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca 2+ -dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50–70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca 2+  homeostasis, and demonstrate that absence of  TMEM38B  causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes.

plos genetics

Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta