Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition

NEUROBIOLOGY OF DISEASE

卷:132

Article

Arystarkhova, Elena¹  Haq, Ihtsham U.²  Luebbert, Timothy³  Mochel, Fanny^4,5  Saunders-Pullman, Rachel⁶  Bressman, Susan B.⁶  Feschenko, Polina¹  Salazar, Cynthia¹  Cook, Jared F.²  Demarest, Scott³  Brashear, Allison²  Ozelius, Laurie J.⁷  Sweadner, Kathleen J.¹ 

[1] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[2] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC 27101 USA

[3] Univ Colorado, Dept Pediat, Sect Neurol, Denver, CO 80202 USA

[4] La Pitie Salpetriere Univ Hosp, AP HP, Dept Genet, Paris, France

[5] UPMC Univ Paris 06, Sorbonne Univ,ICM,INSERM, CNRS,UMR 7225,UMR S 1127,Inst Cerveau & Moelle Ep, U1127,Reference Ctr Adult Neurometab Dis, Paris, France

[6] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[7] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA

关键词: Dystonia;    Ataxia;    Epilepsy;    Neurodegeneration;    Mutation validation;    Phenotype-genotype relationship;    Cytopathology;   

DOI  :  10.1016/j.nbd.2019.104577

来源: Elsevier

【 摘 要 】

Dominant mutations of ATP1A3, a neuronal Na,K-ATPase alpha subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of alpha beta complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (alpha 3) and endogenous ATP1A1 (alpha 1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.

【 授权许可】

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