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Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2

Nature Genetics volume 33, pages 192–196 (2003)Cite this article

Abstract

Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries1,2. About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache3. Although the mode of transmission is controversial4, population-based and twin studies have implicated genetic factors, especially in migraine with aura5,6. Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the α2 subunit of the Na+/K+ pump are associated with familial hemiplegic migraine type 2 (FHM2) linked to chromosome 1q23 (OMIM 602481). Functional data indicate that the putative pathogenetic mechanism is triggered by a loss of function of a single allele of ATP1A2. This is the first report associating mutations of Na+K+ pump subunits to genetic diseases.

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Figure 1: Detection of mutations in ATP1A2.
Figure 2: Local amino acid sequence alignment of ATPases.
Figure 3: ATP1A2 protein topology.
Figure 4: Ouabain treatment of transfected HeLa cells.
Figure 5: Time course of ouabain toxicity.
Figure 6: Localization of mutant ATP1A2 to the plasma membrane.

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Acknowledgements

We thank the individuals with FHM for participating and I. Bernascone for assistance in mutation screening. This work was partially supported by the Italian Telethon Foundation and the Agarini Foundation. This work was carried out in the framework of the Italian Ministry of Research Center of Excellence in Physiopathology of Cell Differentiation.

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Author notes

  1. Maurizio De Fusco and Roberto Marconi: These authors contributed equally to this work

Authors and Affiliations

  1. Human Molecular Genetics Unit, Dibit–San Raffaele Scientific Institute, Via Olgettina 58, Milan, 20132, Italy

    Maurizio De Fusco, Laura Silvestri, Luigia Atorino, Luca Rampoldi, Paolo Aridon & Giorgio Casari

  2. Department of Neurology, Misericordia Hospital, Grosseto, Italy

    Roberto Marconi

  3. Department of Neurosciences, University of Messina, Messina, Italy

    Letterio Morgante

  4. Telethon Institute of Genetics and Medicine and Faculty of Medicine, II University, Naples, Italy

    Andrea Ballabio

  5. Institute of Neuropsychiatry, University of Palermo, Palermo, Italy

    Paolo Aridon

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  1. Maurizio De Fusco
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Correspondence to Giorgio Casari.

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Fusco, M., Marconi, R., Silvestri, L. et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33, 192–196 (2003). https://doi.org/10.1038/ng1081

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