A novel mutation in isoform 3 of the plasma membrane Ca²⁺ pump impairs cellular Ca²⁺ homeostasis in a patient with cerebellar ataxia and laminin subunit 1α mutations

The particular importance of Ca²⁺ signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca²⁺ ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca²⁺. A genetic defect of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation in the ATP2B3 gene in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca²⁺ ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca²⁺ transients generated by cell stimulation and impairs its Ca²⁺ extrusion function under conditions of low resting cytosolic Ca²⁺ as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca²⁺-bound state. The patient also carries two missense mutations in LAMA1, encoding laminin subunit 1α. Onthe basis of the family pedigree of the patient, the presence of both PMCA3 and laminin subunit 1α mutations appears to be necessary for the development of the disease. Considering the observed defect in cellularCa²⁺ homeostasisandthe previous finding that PMCAs act as digenic modulators in Ca²⁺-linked pathologies, the PMCA3 dysfunction along with LAMA 1 mutations could act synergistically to cause the neurological phenotype.