Genetic Variation in <i>KIFAP3</i> Is Associated with an Upper Motor Neuron-Predominant Phenotype in Amyotrophic Lateral Sclerosis

Abstract

Background: Some authors have recently reported that the CC genotype of single-nucleotide polymorphism (SNP) rs1541160 mapping within the kinesin-associated protein 3 (KIFAP3) gene is associated with increased survival in sporadic amyotrophic lateral sclerosis (sALS). Objective and Methods: The relationship between the rs1541160 genotype and several clinical features of 228 ALS patients was evaluated with the intent of assessing any association between the ALS phenotype and KIFAP3. The SNP rs1541160 within the KIFAP3 expression profile was investigated using real-time PCR in a group of 6 patients harboring the CC genotype and in 12 patients harboring the TT genotype. Results: Analysis of our patients’ clinical features showed that almost half of those with the CC genotype were classified as having upper motor neuron-predominant ALS (UMN-ALS). Conversely, there was an approximately 10% frequency of UMN-ALS in both the TT and the TC patient groups as well as in the entire cohort considered as a whole (p < 0.005). The SNP rs1541160 genotype did not appear to have any effect on patient survival or on KIFAP3 expression. Conclusions: The incidence of the UMN-ALS phenotype in the CC patients of this cohort supports the hypothesis that the SNP rs1541160 within the KIFAP3 gene is a potential modifier of the ALS phenotype.

ZNF512B gene is a prognostic factor in patients with amyotrophic lateral sclerosis

“…This study revealed that the survival probability of patients with the risk allele (rs2275294, C allele) in the ZNF512B gene was significantly lower than that in those without the risk (C) allele. The attempts to establish the genetic basis of survival for sALS by identifying susceptibility genes have had little success [18,19]. To date results from candidate gene studies have identified several susceptibility genes [20], although the mechanism by which risk is conferred is not known [13].…”

The genetics and neuropathology of amyotrophic lateral sclerosis

“…Variation in the KIFAP3 gene has been associated with survival in a GWAS study [63], but this was not replicated in a subsequent study [110], although association with the primary lateral sclerosis (PLS) phenotype was [86]. PLS is itself known to have a much better prognosis than typical ALS, and it may be that this is the mechanism by which the original association occurred.…”

Hnrpab regulates neural development and neuron cell survival after glutamate stimulation

“…S4). The decreased protein, Kifap3/KAP3, is a kinesin interacting protein involved in anterograde vesicular transport in glutamatergic neurons and is a genetic modifier of ALS in humans (Choi et al 2008;Orsetti et al 2011). Results from the proteomic analysis demonstrated that Hnrpab regulates expression of many genes that play important roles in the development of the nervous system.…”