Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0028738 (
nystagmus
)
7,431
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The neuron-restricted isoform 3 of the plasma membrane Ca
2+
ATPase plays a major role in the regulation of Ca
2+
homeostasis in the brain, where the precise control of Ca
2+
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 Ca
2+
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 Ca
2+
-linked pathologies.
...
PMID:A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect. 2880 51
