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No association between polymorphisms in the BDNF gene and age at onset in Huntington disease

DOI: 10.1186/1471-2350-7-79

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Abstract:

Five selected tagging polymorphisms were genotyped across a 65 kb region comprising the BDNF gene in a well established cohort of 250 unrelated German HD patients.Addition of BDNF genotype variations or one of the marker haplotypes to the effect of CAG repeat lengths did not affect the variance of the AO.We were unable to verify a recently reported association between the functional Val66Met polymorphism in the BDNF gene and AO in HD. From our findings, we conclude that neither sequence variations in nor near the gene contribute significantly to the variance of AO.Conclusive evidence indicates that brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of Huntington disease (HD). As the protein huntingtin (htt) directly modulates the expression of neuron-restrictive silencer factor (NRSF)-controlled genes, wild type (wt) htt stimulates the production of BDNF, whereas mutant htt causes the opposite effect [1]. It has been shown recently in transgenic mice that BDNF has an impact on the age at onset (AO) and the severity of motor dysfunction by controlling survival of striatal projection neurons [2].The BDNF gene consists of five alternatively spliced 5' exons and one major 3' exon producing at least six BDNF transcripts leading to three pre-proprotein isoforms which differ in the lengths of the signal peptides. Sequence variations in BDNF may therefore lead to variations in gene expression or protein metabolism causing selective neuronal vulnerability. The single nucleotide polymorphism (SNP) rs6265, producing a valine-to-methionine substitution at codon 66 (Val66Met) in the human BDNF gene appears to exert an effect on intracellular trafficking and activity-dependent secretion of BDNF [3]. Furthermore, Met-BDNF carriers demonstrate substantial relative decreases in hippocampal volume, and Val/Met-BDNF affects the volume of gray matter in the cerebral neocortex of normal humans. Finally Met-BDNF is associated with volume reductions prima

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