Neurodegenerative Disease Alzheimer’s Disease
presence of two previously reported polymorphisms in exon 4 (G/C and T/C), which are in complete linkage disequilibrium, as well as a novel rare polymorphism in exon 2 (C/T). Subsequently, these single nucleotide polymorphisms (SNPs) have been tested in a wide case– control study, but no differences in haplotype frequencies were found.37
Other genes under investigation are related to oxidative stress, a process closely involved in AD pathogenesis. In this regard, genes coding for the nitric oxide synthase (NOS) complex have been screened. The common polymorphism consisting of a T/C transition (T-786C) in NOS3, previously reported to be associated with vascular pathologies, has been tested in AD, but no significant differences with controls were found. Nevertheless, expression of NOS3 in peripheral blood mononuclear cells (PBMCs), from either patients or controls, seems to be influenced by the presence of the C polymorphic allele, and is likely to be dose-dependent, being mostly evident in individuals homozygous for the polymorphic variant. The influence of the polymorphism on NOS3 expression rate supports the hypothesis of a beneficial effect exerted in AD by contributing to lower oxidative damage.38
An additional variant in the NOS3 gene has been extensively investigated in AD patients, although the results are still controversial. It is a common polymorphism consisting of a single base change (G894T), which results in an amino acidic substitution at position 298 of NOS3 (Glu298Asp). Dahiyat et al.39
determined the frequency of the
Glu298Asp variant in a two-stage case–control study, showing that individuals homozygous for the wild-type allele were more frequent in late-onset AD. However, studies in other populations failed to replicate these results.40–43
Guidi et al. correlated this variant with total plasma homocysteine (tHcy) levels in patients with AD and controls, demonstrating that the Glu/Glu genotype is correlated with higher levels of tHcy, which represents a known risk factor for AD, and its frequency was increased in AD patients.44
genotype contributes to increase the risk of developing AD could be mediated by an increase of tHcy.
However, NOS-1 is the isoform most abundantly expressed in the brain. Recent genetic analyses demonstrated that the double mutant genotype of the synonymous C276T polymorphism in exon 29 of the NOS1 gene represents a risk factor for the development of early- onset AD,45
untranslated region of NOS1 is not associated with AD.46
regions implicated in the pathogenesis of schizophrenia as well as AD. The presence of the short (S) allele of NOS1 Ex1f-VNTR represents a risk factor for the development of AD. The effect is cumulative, as in S/S carriers the risk is doubled. Most interestingly, the effect of this allele is likely to be gender-specific, as it was found in females only. In addition, the S allele was shown to interact with the APOE*4 allele in both males and females, increasing the risk of developing AD by more than 10-fold.47
Familial Frontotemporal Lobar Degeneration FTLD is a heterogeneous disease characterised by a strong genetic component in its aetiology, as up to 40% of patients report a family history of the disease in at least one family member.51
In 1994 an
autosomal dominantly inherited form of FTLD with parkinsonism was linked to chromosome 17q21.2.52
Subsequently, other familial forms
of FTLD were found to be linked to the same region, resulting in the denomination ‘frontotemporal dementia and parkinsonism linked to chromosome 17’ (FTDP-17) for this class of diseases.
In 1998, the MAPT gene on chromosome 17q21, which encodes the microtubule associated protein tau, was described as the cause of the disease in these families.53–55
Currently, 44 different mutations
in the MAPT gene have been described in a total of 132 families (
www.molgen.ua.ac.be/). MAPT mutations are either non- synonymous or deletion, silent mutations in the coding region, or intronic mutations located close to the splice-donor site of the intron after the alternatively spliced exon 10.56
Mutations are mainly
As regards possible effects on MAPT mutations, different mechanisms are involved, depending on the type and location of the mutation. Many of them disturb the normal splicing balance, producing altered ratios of the different isoforms. A number of mutations promote the aggregation of tau protein, whereas others enhance tau phosphorylation.58
Thus, the mechanism by which this
However, after the discovery of MAPT as a causal gene for FTDP-17, there were still numerous families with autosomal dominant FTLD genetically linked to the same region of chromosome 17q21, which contains MAPT, but in whom no pathogenic mutations had been identified despite extensive analysis of this gene.59–61
The
whereas the dinucleotide polymorphism in the 3’ The
distribution of a functional polymorphism and a variable number of tandem repeats (VNTR) was analysed in a case–control study.47
The
functional variant considered is located in exon 1c, which is one of the nine alternative first exons (named 1a–1i), resulting in NOS1 transcripts with different 5’ untranslated regions.48
Three SNPs have
been identified in exon 1c, but only the G-84A variant displays a functional effect, as the A allele decreases the transcription levels by 30% in in vitro models.49
Regarding exon 1f, a VNTR polymorphism has
been recently reported in its putative promoter region, termed NOS1 Ex1f-VNTR. This VNTR is highly polymorphic and consists of different numbers of dinucleotides (B–Q), which, according to their bimodal distribution, have been dichotomised into short (B–J) and long (K–Q) alleles for association studies. Both Ex1c G-84A and Ex1f-VNTR are associated with psychosis and prefrontal functioning in a population of patients with schizophrenia.50
Both Ex1c and Ex1f transcripts are found in the hippocampus and the frontal cerebral cortex, i.e. brain 14
neuropathological phenotype in these families was similar to the microvacuolar type observed in a large proportion of idiopathic FTD cases with ubiquitin immunoreactive neuronal inclusions. Moreover, clinically, the disease in these families was consistent with diagnostic criteria for FTLD.3
Sequence analysis of the whole MAPT
Moreover, the minimal region containing the disease gene for this group of families was approximately 6.2Mbp in physical distance. This region, defined by markers D17S1787 and D17S806, is particularly gene-rich, containing around 180 genes. Collectively, these data strongly argued against MAPT and pointed to another gene. Systematic candidate gene sequencing of all remaining genes within the minimal candidate region was performed and after sequencing 80 genes, including those prioritised on known function, the first mutation in the progranulin gene (GRN) was identified. It consists of a 4bp insertion of CTGC between coding nucleotides 90 and 91, causing a frame shift and premature termination in progranulin (C31LfsX34).63 These results have been contemporarily replicated by Cruts et al., who analysed other families with FTLD with ubiquitin-positive inclusion (FTLD-U) disease without MAPT pathology, finding a mutation five base
region failed to find a mutation and tau protein appeared normal in these families.62
EUROPEAN NEUROLOGICAL REVIEW
clustered in exons 9–13, except for two recently identified mutations in exon 1.57
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