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1.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
2.  Novel mutations in ataxia telangiectasia and AOA2 associated with prolonged survival 
Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s–30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14 + 2 T > G and 5825C > T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343–345 and 1398 T > G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability.
PMCID: PMC4017341  PMID: 24090759
3.  The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43 
PLoS Genetics  2014;10(12):e1004803.
Pathological aggregates of phosphorylated TDP-43 characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), two devastating groups of neurodegenerative disease. Kinase hyperactivity may be a consistent feature of ALS and FTLD-TDP, as phosphorylated TDP-43 is not observed in the absence of neurodegeneration. By examining changes in TDP-43 phosphorylation state, we have identified kinases controlling TDP-43 phosphorylation in a C. elegans model of ALS. In this kinome-wide survey, we identified homologs of the tau tubulin kinases 1 and 2 (TTBK1 and TTBK2), which were also identified in a prior screen for kinase modifiers of TDP-43 behavioral phenotypes. Using refined methodology, we demonstrate TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro and promote TDP-43 phosphorylation in mammalian cultured cells. TTBK1/2 overexpression drives phosphorylation and relocalization of TDP-43 from the nucleus to cytoplasmic inclusions reminiscent of neuropathologic changes in disease states. Furthermore, protein levels of TTBK1 and TTBK2 are increased in frontal cortex of FTLD-TDP patients, and TTBK1 and TTBK2 co-localize with TDP-43 inclusions in ALS spinal cord. These kinases may represent attractive targets for therapeutic intervention for TDP-43 proteinopathies such as ALS and FTLD-TDP.
Author Summary
Aggregated proteins are a hallmark of many neurodegenerative diseases. In ALS and FTLD-TDP, these aggregates contain abnormal TDP-43 modified by phosphorylation. Protein phosphorylation normally controls protein activity, stability, or location, but in some neurodegenerative diseases the phosphorylated proteins accumulate in excess. Kinases are the enzymes responsible for protein phosphorylation. We have identified two TDP-43 kinases, TTBK1 and TTBK2, using a novel approach combining reverse genetics and biochemical screening to identify the kinases responsible for changes in TDP-43 phosphorylation. We show TTBK1 and TTBK2 directly phosphorylate TDP-43 in vitro, and control TDP-43 phosphorylation in cellular and simple animal models of ALS. This has uncovered a molecular mechanism by which pathological phosphorylated TDP-43 can occur in disease. To determine whether changes in TTBK1/2 protein are contributing to TDP-43 pathology, we examined diseased brain and spinal cord tissue from patients with ALS or FTLD-TDP. We observed changes in the abundance of TTBK1 and TTBK2 in disease-affected neurons, and the coexistence of TTBK1/2 with phosphorylated TDP-43 aggregates in both FTLD-TDP and ALS. Therefore, increased abundance or activity of TTBK1 or TTBK2 may contribute to the neurodegeneration observed in ALS and FTLD-TDP.
PMCID: PMC4256087  PMID: 25473830
4.  Wnt/β-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells 
Human Molecular Genetics  2013;22(23):4661-4672.
Facioscapulohumeral muscular dystrophy is a dominantly inherited myopathy associated with chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4. DUX4 is encoded within each unit of the D4Z4 array where it is normally transcriptionally silenced and packaged as constitutive heterochromatin. Truncation of the array to less than 11 D4Z4 units (FSHD1) or mutations in SMCHD1 (FSHD2) results in chromatin relaxation and a small percentage of cultured myoblasts from these individuals exhibit infrequent bursts of DUX4 expression. There are no cellular or animal models to determine the trigger of the DUX4 producing transcriptional bursts and there has been a failure to date to detect the protein in significant numbers of cells from FSHD-affected individuals. Here, we demonstrate for the first time that myotubes generated from FSHD patients express sufficient amounts of DUX4 to undergo DUX4-dependent apoptosis. We show that activation of the Wnt/β-catenin signaling pathway suppresses DUX4 transcription in FSHD1 and FSHD2 myotubes and can rescue DUX4-mediated myotube apoptosis. In addition, reduction of mRNA transcripts from Wnt pathway genes β-catenin, Wnt3A and Wnt9B results in DUX4 activation. We propose that Wnt/β-catenin signaling is important for transcriptional repression of DUX4 and identify a novel group of therapeutic targets for the treatment of FSHD.
PMCID: PMC3820129  PMID: 23821646
5.  Two Novel Mutations in ABHD12: Expansion of the Mutation Spectrum in PHARC and Assessment of their Functional Effects 
Human mutation  2013;34(12):1672-1678.
PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, and Cataracts) is a recently described autosomal recessive neurodegenerative disease caused by mutations in the α–β–hydrolase domain-containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377X) mutation. Targeted comparative genomic hybridization detected a 59 kb deletion that encompasses exon 1 of ABHD12 and exons 1–4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient’s asymptomatic mother. qRT-PCR demonstrated ~50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity-based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.
PMCID: PMC3855015  PMID: 24027063
PHARC; ABHD12; GINS1; short stature; endocannabinoid; hydrolase activity
6.  Updates on the Genetics of Neurodegenerative Disorders 
Since the publication in 1998 of the last special issue of JGPN on the genetics of dementia, we have witnessed the completion of the Human Genome Project and an exponential increase in the identification of causative genes in human diseases. This special issue revisits the 6 neurodegenerative disorders described in that issue, offering important updates to the genetic findings for these disorders that together comprise the most common causes of dementia among elderly people. It is critical for practicing neurologists, psychiatrists, and geriatricians to keep abreast of these advances as they will impact the clinical diagnosis and management of these disorders. The reviews in this issue have been written by an outstanding group of international experts who provide a clear and insightful update on the molecular genetic advances and genetic counseling principles for each disorder
PMCID: PMC4239989  PMID: 20923756
genetics; neurodegeneration; dementia
7.  TOMM40 intron 6 poly-T length, age-at-onset and neuropathology of AD in individuals with APOE ε3/ε3 
This study investigates the association between TOMM40 poly-T length, age-at-onset, and neuropathology in Alzheimer’s disease (AD) individuals with the APOE ε3/ε3 allele.
Thirty-two PSEN1 mutation carriers with AD, 27 PSEN2 mutation carriers with AD, 59 participants with late-onset AD (LOAD), and 168 participants with autopsies from a community-based cohort were genotyped for TOMM40 intron 6 poly-T (rs10524523) length using short tandem repeat assays.
Among AD patients with PSEN2 mutations, the presence of a long poly-T was associated with an earlier age-at-onset, whereas there were no such associations for patients with PSEN1 mutations or LOAD. In community-based participants, the presence of a long poly-T was associated with increased neuritic tangles and a higher likelihood of pathologically diagnosed AD.
TOMM40 intron 6 poly-T length may explain some of the variation in age-at-onset in PSEN2 familial AD and may be associated with AD neuropathology in persons with APOE ε3/ε3.
PMCID: PMC3606272  PMID: 23183136
Alzheimer’s disease; age-at-onset; genetic; APOE; TOMM40; PSEN1 mutation; PSEN2 mutation; neuropathology
8.  Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS) 
Human Molecular Genetics  2013;22(16):3259-3268.
We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2–X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations.
PMCID: PMC3723311  PMID: 23595882
9.  CDC7 inhibition blocks pathological TDP-43 phosphorylation and neurodegeneration 
Annals of neurology  2013;74(1):39-52.
Kinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions containing hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. Dual phosphorylation of TDP-43 at serines 409/410 drives neurotoxicity in disease models; therefore, TDP-43 specific kinases are candidate targets for intervention.
To find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic C. elegans.
We show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. In FTLD-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathology found in frontal cortex. Furthermore PHA767491, a small molecule inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43 dependent neurodegeneration in TDP-43 transgenic animals.
Taken together these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies including FTLD-TDP and ALS.
PMCID: PMC3775949  PMID: 23424178
amyotrophic lateral sclerosis (ALS); frontotemporal lobar degeneration (FTLD); TDP-43; Tardbp; neurodegeneration; neurotoxicity; neuroprotection; CDC7; TTBK1; TTBK2; kinase; phosphorylation; PHA767491
10.  Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer's disease 
Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer's disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the concordance and discordance of clinical presentation and neuropathology in three MZ twin pairs with AD.
The MZ twins were identified and characterised by the University of Washington Alzheimer's Disease Research Center. We reviewed the available clinical and neuropathological records for all six cases looking specifically for concordance and discordance of clinical phenotype, neuritic amyloid plaques (NP), neurofibrillary tangles (NFT) and Lewy related pathology (LRP).
Discordance in age of onset for developing AD in the MZ twins varied from 4 to 18 years. Clinical presentations also differed between twins. One twin presented with a dementia with Lewy Body clinical syndrome while the other presented with typical clinical AD. Neuropathology within the MZ twin pairs was concordant for NP and NFT, regardless of duration of disease, and was discordant for LRP. This difference was most marked in the late onset AD twin pair. One pair was found to have a mutation in presenilin‐1 (PS1) (A79V) with remarkably late onset in a family member.
MZ twins with AD can vary considerably in age of onset, presentation and disease duration. The concordance of NP and NFT pathological change and the discordance of LRP support the concept that, in AD, the former are primarily under genetic control whereas the latter (LRP) is more influenced by disease duration and environmental factors. The A79V mutation in PS1 can be associated with very late onset of dementia.
PMCID: PMC2117553  PMID: 17615170
11.  Age-Specific Incidence Rates for Dementia and Alzheimer Disease in NIA-LOAD/NCRAD and EFIGA Families 
JAMA neurology  2014;71(3):315-323.
Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD.
To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies.
Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study.
Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD.
The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71).
The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease–related genes in these families or shared environmental risks.
PMCID: PMC4000602  PMID: 24425039
12.  Genome scan in familial late-onset Alzheimer’s disease: a locus on chromosome 6 contributes to age at onset 
Alzheimer’s disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early-onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age-at-onset. Here we present the first genome-scan analysis of the complete, well-characterized University of Washington LOAD sample of 119 pedigrees, using age-at-onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age-at-onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12-14, and 19p13.12. These results provide the first independent confirmation of an AD age-at-onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted.
PMCID: PMC3654841  PMID: 23355194
linkage analysis; MCMC; oligogenic; dementia; age-censored
13.  Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the proteolipid protein 1 
Acta neuropathologica  2009;118(4):10.1007/s00401-009-0562-8.
Mutations affecting proteolipid protein 1 (PLP1), the major protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus–Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.
PMCID: PMC3876935  PMID: 19562355
14.  A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult 
Human Molecular Genetics  2012;21(26):5472-5483.
The autosomal dominant spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders exhibiting cerebellar atrophy and Purkinje cell degeneration whose subtypes arise from 31 distinct genetic loci. Our group previously published the locus for SCA26 on chromosome 19p13.3. In this study, we performed targeted deep sequencing of the critical interval in order to identify candidate causative variants in individuals from the SCA26 family. We identified a single variant that co-segregates with the disease phenotype that produces a single amino acid substitution in eukaryotic elongation factor 2. This substitution, P596H, sits in a domain critical for maintaining reading frame during translation. The yeast equivalent, P580H EF2, demonstrated impaired translocation, detected as an increased rate of −1 programmed ribosomal frameshift read-through in a dual-luciferase assay for observing translational recoding. This substitution also results in a greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge with dithiothreitol or heat shock in our yeast model system. Our results present a compelling candidate mutation and mechanism for the pathogenesis of SCA26 and further support the role of proteostatic disruption in neurodegenerative diseases.
PMCID: PMC3516132  PMID: 23001565
15.  The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ 
The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer’s disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.
Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.
In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
PMCID: PMC4226306  PMID: 24252272
Familial Alzheimer’s disease; Arctic AβPP mutation; β-amyloid peptide; Mass spectrometry; Truncation of Aβ; Topography of Aβ; Hyperphosphorylated tau; Neuronal damage
16.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases 
Coppola, Giovanni | Chinnathambi, Subashchandrabose | Lee, Jason JiYong | Dombroski, Beth A. | Baker, Matt C. | Soto-Ortolaza, Alexandra I. | Lee, Suzee E. | Klein, Eric | Huang, Alden Y. | Sears, Renee | Lane, Jessica R. | Karydas, Anna M. | Kenet, Robert O. | Biernat, Jacek | Wang, Li-San | Cotman, Carl W. | DeCarli, Charles S. | Levey, Allan I. | Ringman, John M. | Mendez, Mario F. | Chui, Helena C. | Le Ber, Isabelle | Brice, Alexis | Lupton, Michelle K. | Preza, Elisavet | Lovestone, Simon | Powell, John | Graff-Radford, Neill | Petersen, Ronald C. | Boeve, Bradley F. | Lippa, Carol F. | Bigio, Eileen H. | Mackenzie, Ian | Finger, Elizabeth | Kertesz, Andrew | Caselli, Richard J. | Gearing, Marla | Juncos, Jorge L. | Ghetti, Bernardino | Spina, Salvatore | Bordelon, Yvette M. | Tourtellotte, Wallace W. | Frosch, Matthew P. | Vonsattel, Jean Paul G. | Zarow, Chris | Beach, Thomas G. | Albin, Roger L. | Lieberman, Andrew P. | Lee, Virginia M. | Trojanowski, John Q. | Van Deerlin, Vivianna M. | Bird, Thomas D. | Galasko, Douglas R. | Masliah, Eliezer | White, Charles L. | Troncoso, Juan C. | Hannequin, Didier | Boxer, Adam L. | Geschwind, Michael D. | Kumar, Satish | Mandelkow, Eva-Maria | Wszolek, Zbigniew K. | Uitti, Ryan J. | Dickson, Dennis W. | Haines, Jonathan L. | Mayeux, Richard | Pericak-Vance, Margaret A. | Farrer, Lindsay A. | Ross, Owen A. | Rademakers, Rosa | Schellenberg, Gerard D. | Miller, Bruce L. | Mandelkow, Eckhard | Geschwind, Daniel H.
Human Molecular Genetics  2012;21(15):3500-3512.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
PMCID: PMC3392107  PMID: 22556362
17.  A novel mutation in FHL1 in a family with X-linked scapuloperoneal myopathy: phenotypic spectrum and structural study of FHL1 mutations 
An X-linked myopathy was recently associated with mutations in the four-and-a-half-LIM domains 1 (FHL1) gene. We identified a family with late onset, slowly progressive weakness of scapuloperoneal muscles in three brothers and their mother. A novel missense mutation in the LIM2 domain of FHL1 (W122C) co-segregated with disease in the family. The phenotype was less severe than that in other reported families. Muscle biopsy revealed myopathic changes with FHL1 inclusions that were ubiquitin- and desmin-positive. This mutation provides additional evidence for X-linked myopathy caused by a narrow spectrum of mutations in FHL1, mostly in the LIM2 domain. Molecular dynamics (MD) simulations of the newly identified mutation and five previously published missense mutations in the LIM2 domain revealed no major distortions of the protein structure or disruption of zinc binding. There were, however, increases in the nonpolar, solvent-accessible surface area in one or both of two clusters of residues, suggesting that the mutant proteins have a variably increased propensity to aggregate. Review of the literature shows a wide range of phenotypes associated with mutations in FHL1. However, recognizing the typical scapuloperoneal phenotype and X-linked inheritance pattern will help clinicians arrive at the correct diagnosis.
PMCID: PMC3016010  PMID: 20633900
X-linked myopathy; scapuloperoneal; FHL1; neurogenetics; muscular dystrophy; genetic diagnosis
18.  Novel antibody capture assay for paraffin-embedded tissue detects wide-ranging amyloid beta and paired helical filament–tau accumulation in cognitively normal older adults 
Quantifying antigens in formalin-fixed tissue is challenging and limits investigation in population-based studies of brain aging. To address this major limitation, we have developed a new technique that we call “Histelide”: immunohistochemistry (HIST-) and ELISA (-EL-) performed on a glass slide (-IDE). We validated Histelide in sections of prefrontal cortex from 20 selected cases: 12 subjects with clinically and neuropathologically diagnosed Alzheimer’s disease (AD), either autosomal dominant or late-onset forms, and 8 clinical and neuropathologic Controls. AD cases had significantly increased amyloid beta (Aβ) peptide and paired helical filament– (PHF-) tau per area of neocortex that was proteinase K-sensitive, and significantly decreased amount of synaptophysin. We next investigated prefrontal cortex from 81 consecutive cases of high cognitive performers from the Adult Changes in Thought (ACT) study, a population-based study of brain aging and incident dementia. As expected, latent AD was common in this group; however, our results quantified widely individually-varying levels of Aβ peptides and PHF-tau among these high cognitive performers. This novel approach obtains quantitative data from population-based studies, and our initial studies with high cognitive performers provide important quantitative insights into latent AD that should help guide expectations from neuroimaging and prevention studies.
PMCID: PMC3295908  PMID: 21999410
19.  Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy 
Human mutation  2012;33(6):949-959.
Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
PMCID: PMC3374402  PMID: 22396310
centronuclear myopathy; congenital myopathy; Charcot–Marie–Tooth neuropathy; DNM2; ADCNM; CMTD1B; DI-CMTB; CMT2M; hereditary motor and sensory neuropathy type II; HMSNII; MTM1; myotubular myopathy; BIN1; RYR1; endocytosis
20.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
PMCID: PMC3510344  PMID: 23143602
21.  Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2 
Brain  2010;133(4):1143-1154.
Mutations in presenilin 2 are rare causes of early onset familial Alzheimer’s disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world’s literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years ± 7.8 (range 39–75) and mean age at death of 64.2 years ± 9.8 (range 43–88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer’s disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination. We conclude that mutations in presenilin 2 are rare with only seven being well documented in the literature. The best studied N141I mutation produces an Alzheimer’s disease phenotype with a wide range of onset ages overlapping both early and late onset Alzheimer’s disease, often associated with seizures, high penetrance and typical Alzheimer’s disease neuropathology. A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer’s disease.
PMCID: PMC2850581  PMID: 20375137
Alzheimer’s disease; presenilin 2; human genetics; dementia; amyloid; Volga German
22.  Autosomal Dominant Familial Dyskinesia and Facial Myokymia: Single Exome Sequencing Identifies a Mutation in Adenylate Cyclase 5 
Archives of neurology  2012;69(5):630-635.
Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a five-generation family of German ancestry we previously mapped FDFM to chromosome 3p21-3q21. The 72.5 Mbp linkage region was too large for traditional positional mutation identification.
To identify the gene responsible for FDFM by exome resequencing of a single affected individual.
Design, Setting and Participants
We performed whole exome sequencing in one affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or 1000 Genomes project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in three generations.
The exome contained 23428 single nucleotide variants, of which 9391 were missense, nonsense or splice site alterations. The critical region contained 323 variants, five of which were not present in one of the sequence-databases. Adenylate cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control Caucasian exomes. This residue is highly conserved and the change is nonconservative and predicted to be damaging.
ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence in combination with linkage information to identify causative genes for rare autosomal dominant Mendelian diseases.
PMCID: PMC3508680  PMID: 22782511
23.  The N141I Mutation in PSEN2 
Archives of neurology  2010;67(5):631-633.
To connect a new family with early-onset Alzheimer disease (EOAD) in Germany to the American Volga German pedigrees.
Pedigree molecular genetic analysis.
University Medical Centers in Fulda and Giessen, Germany, and in Seattle, Washington.
The families from Fulda, Germany, and the American Volga German families with EOAD share the same N141I PSEN2 mutation on an identical haplotypic background. This establishes that the N141I mutation occurred prior to emigration of the families from the Hesse region to Russia in the 1760s, and documents that relatives of the original immigrant families are presently living in Germany with the mutation and the disease.
A family with the N141I mutation in PSEN2 that presently lives in Germany has been connected to the haplotype that carries the same mutation in pedigrees descended from the Volga Germans. This raises the possibility that the original patient with Alzheimer disease (Auguste D.), who had EOAD and lived in this same region of Germany, may also have had the PSEN2 N141I mutation.
PMCID: PMC3016011  PMID: 20457965
24.  The Spectrum of Mutations in Progranulin 
Archives of neurology  2010;67(2):161-170.
Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.
To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants.
Case-control study.
Clinical and neuropathology dementia research studies at 8 academic centers.
Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease.
Main Outcome Measures
Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays.
We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history.
Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.
PMCID: PMC2901991  PMID: 20142524
25.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis 
Lancet neurology  2008;7(5):409-416.
TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identifi ed variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
We identified two variants, p.Gly290Ala and p.Gly298Ser, in TARDBP in two familial ALS kindreds and we observed TDP-43 neuropathology in the CNS tissue available from one family. The variants are considered pathogenic mutations because they co-segregate with disease in both families, are absent in ethnically-matched controls, and are associated with TDP-43 neuropathology in several family members.
The p.Gly290Ala and p.Gly298Ser mutations are located in the glycine-rich domain that regulates gene expression and mediates protein-protein interactions; in particular TDP-43 binds to heterogeneous ribonucleoproteins (hnRNPs) via this domain. We postulate that due to the varied and important cellular functions of TDP-43, these mutations may cause neurodegeneration through both gains and losses of function. The finding of TARDBP mutations implicates TDP-43 as an active mediator of neurodegeneration in a novel class of disorders, TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
PMCID: PMC3546119  PMID: 18396105

Results 1-25 (55)