期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1863, 期 12, 页码 3303-3312出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2017.08.006
关键词
Calcium signaling; Plasma membrane calcium ATPases; X-linked cerebellar ataxia; Pump mutation; Phosphomannomutase 2 mutation
资金
- Ministry of University and Research (Bando SIR) [RBSI14C65Z]
- University degli Studi di Padova (Progetto Giovani) [GRIC128SP0]
- University degli Studi di Padova (Progetto di Ateneo) [CALI_SID16_01, CPDA153402]
- European Research Council [260888]
- Italian Ministry of Health, Ricerca Finalizzata [NET-2013-02356160]
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.
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