Sumi Chakraverty

TDP-43 A315T mutation in familial motor neuron disease

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA‐binding protein 43 (TDP‐43) proteinopathies to investigate TDP‐43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP‐43 gene led to the identification of a novel missense mutation, Ala‐315‐Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP‐43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP‐43 function and neurodegeneration. Ann Neurol 2008

HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin‐positive, tau‐negative inclusions caused by a missense mutation in the signal peptide of progranulin

Familial autosomal dominant frontotemporal dementia with ubiquitin‐positive, tau‐negative inclusions in the brain linked to 17q21‐22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow‐up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques.

Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred

We previously have identified a large kindred from Colombia in which Alzheimers disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan–Meier product‐limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE ε4 allele carriers were more likely to develop AD at an earlier age than subjects without the ε4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07–3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26–0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation. Ann Neurol 2003

Extreme cerebrospinal fluid amyloid β levels identify family with late-onset Alzheimer's disease presenilin 1 mutation

Aggregation and deposition of amyloid beta (Aβ) in the brain is thought to be central to the pathogenesis of Alzheimers disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Aβ levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change Aβ levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Aβ levels as an endophenotype for AD.

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin‐positive, tau‐negative inclusions (FTLD‐U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimers Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD‐U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single‐base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency. Hum Mutat 29(4), 512–521, 2008.

Novel haplotypes in 17q21 are associated with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative diseases presenting as atypical parkinsonian disorders, characterized by the presence of tau‐positive neurofibrillary tangles. Recently, an extended haplotype (H1E) of 787.6kb that comprises several genes including MAPT showed increased association with PSP. The objective of this study was to determine the size of the H1E haplotype associated with PSP and CBD in different populations and to identify specific subhaplotypes in the background of H1E haplotype. Nineteen single nucleotide polymorphisms (SNPs) in the 17q21 region were genotyped in two case–control samples. The SNPs that were associated with higher risk for the disease in the homozygous state delimit a region of more that 1Mb. Haplotype analyses in the Spanish sample showed that the most frequent haplotype found among the patients (H1E′), which extends 1.04Mb and contains several genes such as MAPT, CRHR1, IMP5, Saitohin, WTN3, and NSF. A specific subhaplotype (H1E′A) was present in 16% of PSP patients but was not observed in the controls. Furthermore, the H2E′A haplotype, was rarely present in the disease group suggesting that it plays a protective role. The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients. Ann Neurol 2004;56:249–258

Neuropathologic Heterogeneity in HDDD1: A Familial Frontotemporal Lobar Degeneration With Ubiquitin-positive Inclusions and Progranulin Mutation

Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Aβ plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimers spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.

No association between the alpha-2 macroglobulin I1000V polymorphism and Alzheimer's disease

Recent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimers disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.

Association studies using novel polymorphisms in BACE1 and BACE2.

The release of amyloid-β peptide (Aβ) from β-amyloid precursor protein (APP) requires cleavage by β- and γ-secretases. Several groups have identified a candidate for the β-site APP-cleaving enzyme, BACE1, and its homologue BACE2. We sequenced the genes for BACE1 and BACE2 and found several polymorphisms in both genes. Genotyping a large cohort of AD cases and controls has shown no association between AD and the intronic polymorphism in BACE2 while there was a weak association between the BACE1 polymorphism in exon 5 and AD in those carrying the APOE &epsis;4 allele.

Tau polymorphisms are not associated with Alzheimer's disease

Alzheimers disease (AD) is one of a number of neurodegenerative conditions including frontotemporal dementia and progressive supranuclear palsy that are associated with abnormal tau protein aggregates in neurons. Mutations in the tau gene cause familial forms of frontotemporal dementia and alleles of the tau gene have been associated with risk for progressive supranuclear palsy. However, studies evaluating whether polymorphic variation in tau is associated with AD have produced conflicting results. We investigated the role of the tau exon 2 polymorphism in a large sample of AD cases and controls and found no evidence that polymorphic variation in tau is associated AD.