DEPDC5 – Focal Epilepsy

DEPDC5 (HGNC:18423) encodes a GATOR1 complex subunit that negatively regulates mTORC1 signaling. Heterozygous loss-of-function variants in DEPDC5 have been repeatedly identified in patients with focal epilepsy (MONDO_0005384), confirming a dominantly inherited etiology with incomplete penetrance. Genetic screening across familial and sporadic cohorts supports a strong gene–disease relationship.

Inheritance is autosomal dominant with reduced penetrance, as evidenced by pedigree analyses showing pathogenic DEPDC5 variants segregating with focal epilepsy phenotypes in multiple families ([PMID:23542701]). Segregation studies across 82 families revealed pathogenic DEPDC5 variants in 12% of pedigrees, implicating 10 families with multiple affected relatives ([PMID:23542697]).

Case series and cohort studies identified over 18 distinct DEPDC5 loss-of-function variants, including frameshift, nonsense, and splice-site mutations, among 404 unrelated probands with focal epilepsy ([PMID:26505888]). The variant spectrum also encompasses recurrent founder alleles in population-specific cohorts, such as the French-Canadian p.Arg843Ter founder mutation. In a targeted panel of 96 patients, DEPDC5 variants accounted for 3.1% of diagnoses, underscoring clinical utility of gene testing in MRI-negative focal epilepsy ([PMID:36848747]). One representative variant is c.418C>T (p.Gln140Ter).

Functional assays demonstrate that DEPDC5 loss disrupts GATOR1-mediated inhibition of TORC1, leading to constitutive mTORC1 hyperactivation. In vitro evaluation of patient-derived variants confirmed impaired inhibition of TORC1 signaling ([PMID:25366275]). A neuron-specific Depdc5 conditional knockout mouse recapitulates human pathology, showing dysplastic neurons, increased phospho-S6, reactive astrogliosis, spontaneous seizures, and lowered seizure thresholds ([PMID:29274432]).

Clinical screening of GATOR1 genes in focal epilepsy cohorts yields a diagnostic rate of ~3%, guiding precision management including tailored presurgical evaluation and potential mTOR inhibitor therapy. Early genetic diagnosis can influence surgical candidacy and antiepileptic drug selection, with rapamycin showing promise in preclinical models.

Key Take-home: DEPDC5 haploinsufficiency causes autosomal dominant focal epilepsy via mTORC1 hyperactivation; genetic testing enhances diagnosis and informs targeted therapeutic strategies.

References

• Nature genetics • 2013 • Mutations of DEPDC5 cause autosomal dominant focal epilepsies. PMID:23542701
• Annals of neurology • 2016 • Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. PMID:26505888
• Neurobiology of disease • 2018 • A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. PMID:29274432
• Human mutation • 2015 • Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy. PMID:25366275

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