ATP1A2 – Familial Hemiplegic Migraine Type 2

Familial hemiplegic migraine type 2 (FHM2) is a rare autosomal dominant subtype of migraine with aura caused by heterozygous mutations in ATP1A2, encoding the Na⁺/K⁺‐ATPase α2 subunit. The first pathogenic variant, c.1033A>G (p.Thr345Ala), was identified in a Finnish pedigree with recurrent hemiplegic attacks and coma, co-segregating with disease and absent in 132 controls (PMID:15133718).

Subsequent reports include a four-generation Chinese family with 10 affected members harboring c.2284G>A (p.Gly762Ser), predicted deleterious by seven in silico tools, impairing local protein structure and cell viability in MTT assays (PMID:31053037). An adolescent with recurrent hemiparesis, aphasia, seizures and prolonged cortical hyperperfusion carried c.1133C>T (p.Thr378Ile), further supporting ATP1A2’s role in FHM2 (PMID:38379707).

A multi-family study described two Portuguese probands with V362E and P796S mutations; both showed abnormal Na⁺/K⁺‐ATPase function in cell‐survival assays and segregated with hemiplegic migraine and variable neuropsychiatric features (PMID:18028456). Collectively, >23 distinct missense variants have been reported in >20 unrelated FHM2 probands, with multi‐generation segregation in at least three kindreds.

Functional analyses of FHM2 mutants demonstrate a loss‐of‐function mechanism and haploinsufficiency. Introduction of T345A into rat α2 pumps revealed a twofold increase in K⁺ K₀.₅, faster K⁺ deocclusion, and altered E1/E2 equilibrium, consistent with impaired extracellular K⁺ clearance and delayed neuronal repolarization (PMID:15308625). Additional studies across Xenopus oocytes and mammalian cells report variable reductions in pump currents, altered voltage dependence, and mislocalization for multiple ATP1A2 mutations.

Mechanistically, reduced Na⁺/K⁺‐ATPase activity in astrocytes and vascular smooth muscle predisposes to cortical spreading depression via extracellular K⁺ accumulation and enhanced Ca²⁺ sensitization of cerebral arteries. Mouse models carrying G301R demonstrate hypercontractility of middle cerebral arteries and reduced resting CBF, implicating α2‐pump dysfunction in migraine pathophysiology (PMID:29513112).

No major conflicting evidence negates ATP1A2’s role in FHM2, though common migraine association studies have not supported ATP1A2 as a risk factor for polygenic migraine with aura. Overall, genetic and experimental data fulfill the ClinGen criteria for a Definitive gene–disease relationship, with high clinical utility for molecular diagnosis, genetic counseling, and targeted therapeutics.

Key Take-home: ATP1A2 haploinsufficiency underlies FHM2 by impairing Na⁺/K⁺‐ATPase function, and comprehensive genetic testing informs diagnosis and management.

References

• Neurogenetics | 2004 | A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2. PMID:15133718
• Cephalalgia | 2019 | A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2. PMID:31053037
• The Journal of Biological Chemistry | 2004 | Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2. PMID:15308625
• Clinical Genetics | 2008 | Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes. PMID:18028456
• Journal of Cerebral Blood Flow and Metabolism | 2019 | Smooth muscle Ca2+ sensitization causes hypercontractility of middle cerebral arteries in mice bearing the familial hemiplegic migraine type 2 associated mutation. PMID:29513112

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