This article has Open Peer Review reports available.
No association between polymorphisms in the BDNF gene and age at onset in Huntington disease
© Mai et al; licensee BioMed Central Ltd. 2006
Received: 08 August 2006
Accepted: 10 November 2006
Published: 10 November 2006
Recent evidence suggests that brain-derived neurotrophic factor (BDNF) is an attractive candidate for modifying age at onset (AO) in Huntington disease (HD). In particular, the functional Val66Met polymorphism appeared to exert a significant effect. Here we evaluate BDNF variability with respect to AO of HD using markers that represent the entire locus.
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 . 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 .
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 . 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 primarily in the lateral convexity of the prefrontal cortex . Thus, the Val66Met polymorphism may be a modifying genetic factor in the expression of a number of normal and abnormal brain conditions, and therefore represents a good candidate gene for modifying AO in HD. In this context, several associations between BDNF polymorphisms and neurological and psychiatric disorders have been reported . In addition, a recent study demonstrated that HD patients heterozygous for the Val66Met polymorphism present a later AO than homozygous carriers of Val-BDNF .
In this study, we investigated the relation between the BDNF gene and the AO of HD using genetic markers that represent the overall variability at this locus.
We selected tagging polymorphisms from the BDNF gene (rs6265, rs11030104, rs7103873, rs2049046 and rs12273363) based on HapMap data. We examined the associations between BDNF polymorphisms and motor AO of HD in 250 unrelated patients with clinical diagnosis of HD as recruited from the Huntington Center (HZ) NRW, Bochum (Germany) . Informed consent was obtained and the institutional Ethics Committee of Bochum Ruhr-University approved this study.
The expanded CAG repeats explained 50.9% of the variance in AO in this cohort. The potential influence of certain genotypes on AO was calculated by linear regression, in which R2 illustrates the relative improvement of the regression model when the various genotypes are considered in addition to the expanded CAG block in the huntingtin gene.
Results and Discussion
Allele and genotype frequencies of the BDNF polymorphisms
Allele counts (Frequency-%)
Genotype counts (Frequency-%)
In our association study between common polymorphisms that represent the entire variability of the BDNF gene and the variance in motor AO in HD, we were unable to verify the reported association between a single polymorphism at the BDNF gene and AO in HD.
- Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E: Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet. 2003, 35: 76-83. 10.1038/ng1219.View ArticlePubMedGoogle Scholar
- Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P, Alberch J: Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease. J Neurosci. 2004, 24: 7727-7739. 10.1523/JNEUROSCI.1197-04.2004.View ArticlePubMedGoogle Scholar
- Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003, 112: 257-269. 10.1016/S0092-8674(03)00035-7.View ArticlePubMedGoogle Scholar
- Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR: The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci. 2004, 24: 10099-10102. 10.1523/JNEUROSCI.2680-04.2004.View ArticlePubMedGoogle Scholar
- Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, Price LH, Southwick S, Yang BZ, Rasmussen A, Gelernter J: Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet (Neuropsychiatr Genet). 2006, 141: 387-93.View ArticleGoogle Scholar
- Alberch J, Lopez M, Badenas C, Carrasco JL, Mila M, Munoz E, Canals JM: Association between BDNF Val66Met polymorphism and age at onset in Huntington disease. Neurology. 2005, 65: 964-965. 10.1212/01.wnl.0000175977.57661.b1.View ArticlePubMedGoogle Scholar
- Arning L, Kraus PH, Valentin S, Saft C, Epplen JT: NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenet. 2005, 1: 25-28. 10.1007/s10048-004-0198-8.View ArticleGoogle Scholar
- Di Maria E, Marasco A, Tartari M, Ciotti P, Abbruzzese G, Novelli G, Bellone E, Cattaneo E, Mandich P: No evidence of association between BDNF gene variants and age-at-onset of Huntington's disease. Neurobiol Dis. 2006, 2: 274-279. 10.1016/j.nbd.2006.07.002.View ArticleGoogle Scholar
- Kishikawa S, Li JL, Gillis T, Hakky MM, Warby S, Hayden M, Macdonald ME, Myers RH, Gusella JF: Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington's disease. Neurobiol Dis. 2006, 2: 280-285. 10.1016/j.nbd.2006.07.008.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/7/79/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.