TTC3 – Alzheimer Disease

This summary reviews the association between TTC3 (HGNC:12393) and Alzheimer disease (MONDO_0004975). Data from an extended family indicate that a rare, nonsynonymous variant in TTC3 segregates with disease, supporting a strong association. The evidence supporting this association has been derived from both detailed case analyses and multi‐patient studies.

Clinical investigations identified 11 affected individuals in a single extended family, all of whom carried the missense variant c.3113C>G (p.Ser1038Cys) (PMID:27066578). Segregation analyses in this autosomal dominant family yielded a LOD score of 2.66 (PMID:27066578), reinforcing the genetic contribution of TTC3 to Alzheimer disease. Such clear segregation data contribute significantly to the robustness of the gene-disease claim.

Beyond segregation, the genetic evidence is further bolstered by the recurrence of the same variant across the affected subjects. The c.3113C>G (p.Ser1038Cys) alteration is consistently observed in all affected individuals and serves as a compelling marker for the disease phenotype. The autosomal dominant inheritance observed in these families aligns well with the molecular findings, suggesting a consistent pattern of disease transmission.

Experimental evidence has added an important functional dimension to this association. CRISPR/Cas9 approaches were used to introduce the c.3113C>G (p.Ser1038Cys) variant into induced pluripotent stem cell (iPSC)-derived cortical neurons. Functional assays demonstrated that neurons harboring the variant exhibit altered neurite length, increased branching, and changes in synaptic protein expression, which are in line with perturbations in actin cytoskeleton organization and PI3K-Akt signaling (PMID:37677864). These results support a pathogenic mechanism whereby the TTC3 variant disrupts critical neuronal pathways.

It is important to note that although additional functional assessments in different contexts (e.g., Down syndrome) were performed, the core evidence linking TTC3 to Alzheimer disease is derived from robust segregation, genetic, and iPSC-based functional studies. This layered evidence integration enhances confidence in the clinical relevance of TTC3 for late-onset Alzheimer disease.

In summary, the converging genetic and experimental data provide a strong basis for TTC3 as a candidate gene in Alzheimer disease. This association not only guides diagnostic decision‑making but also lays the groundwork for future research and potential therapeutic interventions, underscoring its value in both clinical and commercial settings.

References

• Neurology. Genetics • 2016 • Segregation of a rare TTC3 variant in an extended family with late‑onset Alzheimer disease PMID:27066578
• Neurobiology of Aging • 2023 • An Alzheimer’s disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC‑derived forebrain neurons PMID:37677864

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