Dynamin 2 gene is a novel susceptibility gene for late-onset Alzheimer disease in non-APOE-ε4 carriers

Abstract

Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that b amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a casecontrol study of 429 patients with LOAD and 438 sex-and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-e4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD.

Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

“…It has been reported that DNM2 gene mutation is an important factor for patients with autosomal dominant centronuclear myopathy (20) and Alzheimer's disease (21,22). Recurrent DNM2 mutations have also been identified in patients with ETP-ALL by whole-exome sequencing (6,10,23).…”

Molecular Mechanisms of Presynaptic Membrane Retrieval and Synaptic Vesicle Reformation

“…For example, the PI(4,5)P 2 -phosphatase synaptojanin 1, is overexpressed in Down syndrome resulting in phosphoinositide dyshomeostasis and cognitive disabilities, while reduced synaptojanin 1 levels ameliorate synaptic and behavioral impairments caused by Ab-mediated disruption of PI(4,5)P 2 metabolism in Alzheimer's disease models (McIntire et al, 2012). Moreover, genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the genes encoding for the AP180 paralog CALM, dynamin 2, and amphiphysin 1 in familial and sporadic cases of Alzheimer's disease (Aidaralieva et al, 2008;Harold et al, 2009;Seshadri et al, 2010). Finally, GIT1 (termed dGIT in Drosophila), an AZ-associated scaffold with GTPase activating protein activity toward Arf6, associates with stonin 2/stoned B and regulates SV recycling (Podufall et al, 2014).…”

Adult centronuclear myopathies: A hospital-based study

“…However, as the DNM2 protein is expressed in the brain, one may hypothesize that the subtle brain abnormalities we observed may result from an impaired DNM2 function in brain. In keeping with this concept, it has been recently demonstrated that late-onset Alzheimer's disease is significantly associated with a single nucleotide polymorphism located in the DNM2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele (Aidaralieva et al, 2008). Furthermore, a decrease of dynamin 2 levels has also been observed in lateonset Alzheimer's disease (Kamagata et al, 2009).…”