A 14 bp indel variation in the NCX1 gene modulates the age at onset in late-onset Alzheimer’s disease

Abstract

Calcium homeostasis is critical to amyloid beta precursor protein (APP) processing. Na(+)/Ca(2+) exchanger (NCX) proteins play an important role in maintaining intracellular Na(+) and Ca(2+) homeostasis in the brain under physiological and pathological conditions. We sequenced a hyper-variable region in intron 2 of the Na(+)/Ca(2+) exchanger 1 gene (NCX1), and investigated whether insertion/deletion variations in this region are associated with the occurrence for Alzheimer's disease (AD). Examining 413 AD patients and 361 healthy controls, we identified 3 insertion/deletion polymorphisms. No significant differences of the allele and genotype frequencies were observed between the AD cases and the controls for any of the three polymorphisms. However, among the AD patients whose age at onset (AAO) was 65 years or older (n = 299), carriers of a 14 bp insertion showed a lower average AAO (ins/ins and ins/del vs. del/del, 72.49 ± 5.17 vs. 74.28 ± 5.79, p = 0.016). It suggested that this 14 bp insertion/deletion polymorphism might modulate AAO in late-onset AD patients.

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

“…Three different isoforms of the NCX (NCX1, NCX2 and NCX3) have been characterized, cloned and detected in various tissues, including the central nervous system (Philipson and Nicoll, 1997; Quednau et al, 1997; Papa et al, 2003; Lytton, 2007). The NCX has been implicated in the pathophysiology of various neurological conditions, including Alzheimer’s disease (Bi et al, 2012; Sokolow et al, 2011), ischemia (Pignataro et al, 2004; Lee et al, 2005; Boscia et al, 2006), hypoxia (Secondo et al, 2007) and Parkinson’s disease (Ago et al, 2011). Although the role of the NCX in the pathogenesis of seizures and epilepsy remains poorly understood, we have reported that inhibition of Ca 2+ influx via NCX activity in the reverse mode reduced the incidence of pilocarpine-induced limbic seizures and status epilepticus (Martinez and N’Gouemo, 2010).…”

Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two‐phase study

“…Furthermore, Na + /Ca 2+ exchanger is a major calcium transporter in the kidney . Na + /Ca 2+ exchange disturbance originating from SLC8A1 genetic polymorphisms is a potential mechanism driving the development of cardiovascular disease and Alzheimer's disease . Studies have also indicated that mutations at specific sites within the transmembrane segment of SLC8A1 gene influence Ca 2+ transportation .…”

“…[24][25][26] Na + /Ca 2+ exchange disturbance originating from SLC8A1 genetic polymorphisms is a potential mechanism driving the development of cardiovascular disease [32][33][34][35] and Alzheimer's disease. 36 Studies have also indicated that mutations at specific sites within the transmembrane segment of SLC8A1 gene influence Ca 2+ transportation. 21 In addition to the Na + /Ca 2+ exchanger, K+ recycling through ROMK (encoded by KCNJ1) and NKCC2 encoded by SLC12A1) serve as driving forces for paracellular reabsorption of calcium in the kidney.…”

Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two‐phase study

“…(24-26) Na + /Ca 2+ exchange disturbance originating from SLC8A1 genetic polymorphisms is a potential mechanism driving the development of cardiovascular disease (32)(33)(34)(35)) and Alzheimer's disease. (36) Studies have also indicated that mutations at specific sites within the trans-membrane segment of SLC8A1 gene influence Ca 2+ transportation. (21) In addition to the Na + /Ca 2+ exchanger, K+ recycling through ROMK (encoded by KCNJ1) and NKCC2 (encoded by SLC12A1) serve as driving forces for paracellular reabsorption of calcium in the kidney.…”