TBC1D7 – Intellectual Disability

TBC1D7 is a critical subunit of the TSC1–TSC2 complex that regulates mTORC1 signaling, and emerging evidence now links loss‐of‑function variants in TBC1D7 with a subset of intellectual disability phenotypes without the hallmark features of tuberous sclerosis. Two independent studies in unrelated families have identified homozygous truncating variants in TBC1D7 that segregate with intellectual disability. In one consanguineous family, a rare coding variant (c.322dup (p.Tyr108fs)) was identified in affected siblings, while a second study reported a similar truncating mutation in two affected sisters, establishing an autosomal recessive inheritance pattern (PMID:23687350, PMID:24515783).

Genetic evidence for the association is reinforced by the observation that these loss‑of‑function variants consistently lead to reduced or absent TBC1D7 expression, supporting a mechanism of haploinsufficiency. Detailed case reports indicate not only the presence of intellectual disability but also, in some cases, associated brain overgrowth phenotypes. The identification of c.322dup (p.Tyr108fs) in the patient cohorts directly implicates the disruption of the protein’s normal function in the disease process.

Functional assessments provide further support; cell‐based assays have demonstrated that loss of TBC1D7 results in increased mTORC1 signaling, a pathway known to be intimately involved in neuronal growth and synaptic regulation. Structural studies and cellular models confirm that TBC1D7 is necessary for the stability of the TSC complex, and its disruption appears to specifically impair neurodevelopmental processes without eliciting the broader features typically seen in tuberous sclerosis (PMID:26798146, PMID:26893383).

Notably, while TBC1D7 mutations have also been evaluated in the context of megalencephaly and other non-classic features of tuberous sclerosis, the evidence for an association with intellectual disability remains distinct. The absence of other TSC-related manifestations in affected individuals underscores the specificity of this gene-disease relationship (PMID:23687350).

Overall, the convergence of genetic data from multiple families together with robust functional studies provides a strong basis for considering the association between TBC1D7 loss-of-function and intellectual disability as clinically significant. Although further studies may expand the phenotypic spectrum, current evidence supports the diagnostic evaluation of TBC1D7 in patients with intellectual disability.

Key take‑home: TBC1D7 variants disrupt mTORC1 regulation, and their identification in patients with intellectual disability highlights a specific, actionable target for diagnostic and therapeutic strategies.

References

• Journal of medical genetics • 2013 • Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly PMID:23687350
• Human Mutation • 2014 • TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease PMID:24515783
• Journal of molecular cell biology • 2016 • Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region PMID:26798146
• The Journal of biological chemistry • 2016 • Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7) PMID:26893383
• Cell Reports • 2022 • The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth PMID:35584673

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