A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect

作者：Vicario, Mattia; Cali, Tito; Cieri, Domenico; Vallese, Francesca; Bortolotto, Raissa; Lopreiato, Raffaele; Zonta, Francesco; Nardella, Marta; Micalizzi, Alessia; Lefeber, Dirk J.; Valente, Enza Maria; Bertini, Enrico; Zanotti, Giuseppe; Zanni, Ginevra^*; Brini, Marisa^*; Carafoli, Ernesto^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2017, 1863(12): 3303-3312.

DOI：10.1016/j.bbadis.2017.08.006

• Calcium signaling
• Plasma membrane calcium ATPases
• X-linked cerebellar ataxia
• Pump mutation
• Phosphomannomutase 2 mutation

The neuron-restricted isoform 3 of the plasma membrane Ca2+ ATPase plays a major role in the regulation of Ca2+ homeostasis in the brain, where the precise control of Ca2+ signaling is a necessity. Several function affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies. Here we report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. Biochemical studies of the pump have revealed impaired ability to control cellular Ca2+ handling both under basal and under stimulated conditions. A combined analysis by homology modeling and molecular dynamics have revealed a role for the mutated residue in maintaining the correct 3D configuration of the local structure of the pump. Mutation analysis in the patient has revealed two additional function-impairing compound heterozygous missense mutations (R123Q and G214S substitution) in phosphomannomutase 2 (PMM2), a protein that catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. These mutations are known to be associated with Type Ia congenital disorder of glycosylation (PMM2-CDG), the most common group of disorders of N-glycosylation. The findings highlight the association of PMCA3 mutations to cerebellar ataxia and strengthen the possibility that PMCAs act as digenic modulators in Ca2+-linked pathologies.

• 出版日期2017-12
• 单位上海科技大学