Defective membrane expression of the Na ⁺ -HCO ₃ ⁻ cotransporter NBCe1 is associated with familial migraine

Abstract

Homozygous mutations in SLC4A4 , encoding the electrogenic Na + -HCO 3 − cotransporter NBCe1, have been known to cause proximal renal tubular acidosis (pRTA) and ocular abnormalities. In this study, we report two sisters with pRTA, ocular abnormalities, and hemiplegic migraine. Genetic analysis ruled out pathological mutations in the known genes for familial hemiplegic migraine, but identified a homozygous 65-bp deletion (Δ65bp) in the C terminus of NBCe1, corresponding to the codon change S982NfsX4. Several heterozygous members of this family also presented glaucoma and migraine with or without aura. Despite the normal electrogenic activity in Xenopus oocytes, the Δ65bp mutant showed almost no transport activity due to a predominant cytosolic retention in mammalian cells. Furthermore, coexpression experiments uncovered a dominant negative effect of the mutant through hetero-oligomer formation with wild-type NBCe1. Among other pRTA pedigrees with different NBCe1 mutations, we identified four additional homozygous patients with migraine. The immunohistological and functional analyses of these mutants demonstrate that the near total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…More recently, in some patients suffering from migraine an homozygous mutation in the SLC4A4 gene (NBCe1, encoding the electrogenic Na(+)-HCO(3)(-) co-transporter was found; Suzuki et al 2010). The immunohistological and functional analyses of these mutants demonstrate that the nearly total loss of NBCe1 activity in astrocytes can cause migraine potentially through dysregulation of synaptic pH.…”

Pathophysiological Roles of Mutations in the Electrogenic Na+-HCO - Cotransporter NBCe1

“…Consistent with an essential role of NBCe1 in bicarbonate absorption from renal proximal tubules, homozygous mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) [3][4][5][6][7][8][9][10][11]. These pRTA patients with NBCe1 mutations invariably present with ocular abnormalities such as band keratopathy, cataract, and glaucoma, indicating that NBCe1 also plays important roles in the maintenance of ocular homeostasis [12,13].…”

“…These pRTA patients with NBCe1 mutations invariably present with ocular abnormalities such as band keratopathy, cataract, and glaucoma, indicating that NBCe1 also plays important roles in the maintenance of ocular homeostasis [12,13]. Some pRTA patients also have migraine, suggesting that NBCe1 may also contribute to the pH regulation in the brain [10]. In addition, mice models for NBCe1 deficiency have been developed [11,14].…”

Clinical and laboratory approaches in the diagnosis of renal tubular acidosis

“…Table 1 summarizes the genetic and molecular basis, as well as the clinical, biochemical, and radiological findings useful to identify the subtype of RTA [1][2][3][4][5][6][7][8][9][10][11][12]. Information on acquired forms of RTA secondary to drugs and toxins or associated to systemic diseases is not included because this review mostly deals with congenital primary types of RTA, which are more frequently found in pediatric patients.…”