RESUMO
Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteínas/genética , Adulto , Idade de Início , Esclerose Lateral Amiotrófica/metabolismo , Bélgica , Proteína C9orf72 , Ilhas de CpG/genética , Metilação de DNA/genética , Regulação para Baixo , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Proteínas/metabolismoRESUMO
Familial keratosis palmaris et plantaris (KPPF) is characterized by extreme keratinization and desquamation of the skin of the palmar and plantar surfaces of the hands and feet. We have mapped the causative genetic defect to an 8 cM interval on 17q12-24 in or close to the acidic keratin (type I) gene cluster. We show that KPPF co-segregates with a rare, high molecular weight allele of an insertion-deletion polymorphism in the C-terminal coding region of the keratin 10 gene (Z = 8.36 at theta = 0.00) and segrates as a true autosomal dominant trait. Some pedigrees with familial hyperkeratosis of the palms and soles have co-inherited diseases such as congenital malformations and familial cancers. Our analysis provide a region which should be investigated for contiguous gene syndromes in such pedigrees.
Assuntos
Cromossomos Humanos Par 17 , Queratinas/genética , Ceratodermia Palmar e Plantar/genética , Receptores do Ácido Retinoico/genética , Sequência de Bases , Mapeamento Cromossômico , DNA , Análise Mutacional de DNA , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Receptor alfa de Ácido RetinoicoRESUMO
Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14 , Idoso , Alelos , Precursor de Proteína beta-Amiloide/genética , Sequência de Bases , Mapeamento Cromossômico , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , LinhagemRESUMO
BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.
Assuntos
Glucosilceramidase/genética , Mutação , Doença de Parkinson/genética , Idoso , Estudos de Casos e Controles , Genótipo , Humanos , Judeus/genética , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Razão de ChancesRESUMO
The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Membrana Celular/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais/fisiologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Ácido Aspártico Endopeptidases , Sítios de Ligação/fisiologia , Membrana Celular/ultraestrutura , Células Cultivadas/citologia , Células Cultivadas/metabolismo , Endopeptidases/genética , Endopeptidases/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Mutação/fisiologia , Estrutura Terciária de Proteína/fisiologia , Receptores Notch , TransfecçãoRESUMO
The presenilin proteins are components of high-molecular-weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain beta-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of beta-catenin after activation of the Wnt/beta-catenin signal transduction pathway. As with their effect on betaAPP processing, the effect of PS1 mutations on trafficking of beta-catenin arises from a dominant 'gain of aberrant function' activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin-beta-catenin protein complexes is central to this process.
Assuntos
Doença de Alzheimer/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas de Membrana/genética , Mutação , Transativadores , Doença de Alzheimer/metabolismo , Transporte Biológico/genética , Linhagem Celular , Núcleo Celular/metabolismo , Humanos , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Presenilina-1 , Presenilina-2 , Ligação Proteica , Transdução de Sinais/genética , beta CateninaRESUMO
OBJECTIVE: It is generally acknowledged that at least 50% of individuals with amyotrophic lateral sclerosis (ALS) will exhibit cognitive deficits outside of the characteristic motor neuron involvement. However, a specific cognitive profile has been difficult to ascertain due to disease-related testing barriers and limitations in the sensitivity and specificity of available assessment methods. This study assessed the level of functioning of extramotor frontal cognitive processes in ALS, and the amount of change in the functioning in these processes over time as disease progresses. METHODS: Empirical tests validated for a model of frontal lobe functioning were modified into an assessment battery appropriate for individuals with ALS in a clinical setting (the ALS-CFB, Computerised Frontal Battery). Twenty ALS participants and 36 age- and education-matched neurologically healthy controls were tested, and a sub-sample of each group (11 ALS and 20 controls) re-tested after approximately nine months. RESULTS AND CONCLUSIONS: Compared to standard neuropsychological screening tests that did not show a difference between ALS participants and healthy controls, the ALS-CFB illustrated a profile of extramotor frontal dysfunction involving energisation (preparing the neural system to respond) and executive functions, a profile that may be indicative of the nature of neurodegeneration in ALS.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/psicologia , Cognição , Lobo Frontal/fisiopatologia , Idade de Início , Idoso , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Progressão da Doença , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tempo de Reação , Movimentos Sacádicos , Percepção Social , Teoria da MenteRESUMO
Numerous missense mutations in the presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, unfolded protein responses and processing of selected proteins including the beta-amyloid precursor protein. Although the underlying mechanism by which presenilin mutations lead to development of Alzheimer disease remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid beta-peptides. Furthermore, presenilins interact with beta-catenin to form presenilin complexes, and the physiological and mutational effects are also observed in the catenin signal transduction pathway.
Assuntos
Doença de Alzheimer/etiologia , Proteínas de Membrana/fisiologia , Transativadores , Doença de Alzheimer/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Hipocampo/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Presenilina-1 , Presenilina-2 , Transdução de Sinais , beta CateninaRESUMO
Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant presenilin holoproteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional presenilin moieties are contained in the high molecular weight presenilin NTF/CTF-containing complexes.
Assuntos
Doença de Alzheimer/fisiopatologia , Ácido Aspártico/metabolismo , Proteínas de Membrana/genética , Mutação Puntual , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/genética , Ácido Aspártico Endopeptidases , Técnicas de Cultura de Células , Membrana Celular , DNA Complementar/genética , Endopeptidases/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Presenilina-1 , Presenilina-2 , Conformação ProteicaRESUMO
Two children of an adult with early-onset, autopsy-confirmed Alzheimer disease (AD) developed dementia in their late 20s and were subsequently found to have novel mutations in codon 434 of the presenilin 1 (PS1) gene on chromosome 14, a G-to-T substitution at nucleotide 1548 and a C-to-G substitution at nucleotide 1549. The younger of the 2 children had AD confirmed at postmortem examination. The disease course in these 3 individuals was characterized by cognitive and behavioral problems accompanied by myoclonus, seizures, and aphasia within 5 years after onset. Two grandparents had clinically diagnosed AD with stroke beginning at ages 78 and 66 years, but neither had a PS1 mutation. No other living family member was demented, nor did any other family member have the PS1 mutation. We conclude that the affected parent of the proband was a likely recent founder for these novel mutations in PS1. The family demonstrates the clinical and genetic heterogeneity of AD. Arch Neurol. 2000;57:1454-1457
Assuntos
Doença de Alzheimer/genética , Proteínas de Membrana/genética , Mutação Puntual/genética , Adulto , Distribuição por Idade , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Cromossomos Humanos Par 14/genética , Códon/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Emaranhados Neurofibrilares/metabolismo , Linhagem , Presenilina-1RESUMO
BACKGROUND: Angiotensin-converting enzyme has been reported to show altered activity in patients with neurologic diseases. An insertion-deletion polymorphism in ACE has recently been linked to heart disease, cerebrovascular disease, and AD. OBJECTIVE: To determine whether the angiotensin-converting enzyme (ACE) is associated with risk of Alzheimer disease (AD). METHODS: We investigated the ACE polymorphism as a potential risk factor for AD in 151 patients with AD and 206 ethnically matched controls from Russia and in 236 patients with AD and 169 controls from North America by means of allele association methods and logistic regression. RESULTS: None of the ACE genotypes was associated with increased susceptibility to AD in the total sample or in subsets stratified by apolipoprotein E gene (APOE) epsilon4 status. However, the D allele was more frequent among AD cases between ages 66 and 70 years compared with controls in both the Russian (P = .02) and North American (P = .001) datasets. In this age group, the effect of D (odds ratio, 11.2; 95% confidence interval, 2.9-44.0) appeared to be independent of and equal or greater in magnitude to the effect of APOE epsilon4 (odds ratio, 7.8; 95% confidence interval, 3.5-7.4). CONCLUSIONS: Our results suggest that APOE and ACE genotypes may be independent risk factors for late-onset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed.
Assuntos
Doença de Alzheimer/enzimologia , Peptidil Dipeptidase A/metabolismo , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , DNA/análise , DNA/genética , Primers do DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Moscou/epidemiologia , Ontário/epidemiologia , Peptidil Dipeptidase A/genética , Fatores de RiscoRESUMO
BACKGROUND: Seven loci for autosomal dominant hereditary spastic paraplegia (ADHSP) have been mapped. To date, two families of SPG12 (chromosome 19q13) have been analyzed; however, there is not enough clinical information on SPG12 to establish locus-phenotype correlations. METHODS: The authors studied 60 individuals from a large Italian family with ADHSP, in which 16 members in four generations were affected. They performed genetic linkage analysis with DNA markers from currently known ADHSP loci. After database searching, one candidate gene for SPG12 was analyzed by sequencing. RESULTS: The patients in this family showed an early onset and rapid progression of symptoms, resulting in severe disability, with a large proportion of affected members requiring use of a wheelchair. By age 16, most patients had sensory disturbance. Evidence for linkage to the SPG12 locus was obtained. Obligate recombination events observed in this family have narrowed the SPG12 locus from the 16.1 cM to 11.3 cM region between markers D19S416 and D19S412. In combination with previous genetic studies, the SPG12 locus was further narrowed to the 3.3 cM region between D19S416 and D19S220. A homologue of the AAA (ATPases associated with a variety of cellular activities) protein family, proteasome 26S subunit ATPase mapped near D19S220, was excluded by sequencing. CONCLUSIONS: This study refined the SPG12 region between D19S416 and D19S220 and revealed several clinical characteristics-early onset, rapid progression, and involvement of sensory disturbance-that may be unique to SPG12. Suggestive evidence of genetic anticipation was obtained, but should be confirmed in other SPG12 families.
Assuntos
Cromossomos Humanos Par 19 , Ligação Genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Adenosina Trifosfatases/genética , Adolescente , Adulto , Saúde da Família , Feminino , Humanos , Itália , Masculino , Linhagem , Fenótipo , EspastinaRESUMO
OBJECTIVE: To describe the clinical features, neuropathology, and genetic studies in a family with autosomal dominant frontotemporal dementia (FTD). BACKGROUND: Clinical Pick's disease, or FTD with parkinsonism, has been described in several families linked to chromosome 17 (FTDP-17). Most of these have shown tau protein mutations. The clinical and pathologic variations in these families resemble the spectrum of sporadic FTD or "Pick complex." METHODS: Clinical and behavioral analysis of the affected members with extensive histochemical and neuropathologic description of three cases, genetic analysis of three clinically affected members and seven at risk members to assess linkage to chromosome 17, and sequencing of the tau gene in two patients were performed. RESULTS: The clinical pattern shows a highly stereotypic disinhibition dementia with late extrapyramidal features, progressive mutism, and terminal dysphagia in three generations of affected individuals. Neuropathology showed frontotemporal atrophy, and microscopically tau- and synuclein-negative and ubiquitin-positive neuronal inclusions, in the background of superficial cortical spongiosis, neuronal loss, and gliosis. Tau expression was restricted to oligodendroglia. All exons and surrounding introns of the tau gene were sequenced, and no mutation or disease-related polymorphisms were detected in either of two affected pedigree members. CONCLUSION: This family with autosomal dominant frontotemporal dementia (FTD) shows no tau expression in neurons. The ubiquitin-positive, tau-negative inclusions have been described before in FTD with and without motor neuron disease, but not in a familial form. The clinical and some pathologic features are similar to those of several of the families included in descriptions of FTD with parkinsonism linked to chromosome 17, but the linkage to tau has been excluded. The defect in this family, however, could be functionally related to tau mutations.
Assuntos
Demência/genética , Demência/patologia , Lobo Frontal/patologia , Corpos de Inclusão/patologia , Lobo Temporal/patologia , Ubiquitinas/análise , Proteínas tau/análise , Adulto , Humanos , Imuno-Histoquímica , Masculino , Linhagem , FenótipoRESUMO
BACKGROUND: Mutations in the presenilin-1 gene (PS1) account for a majority of patients with early-onset familial AD. However, the clinical indications and algorithms for genetic testing in dementia are still evolving. METHODS: The entire open reading frame of the PS1 gene was sequenced in a series of 414 consecutive patients referred for diagnostic testing, including 372 patients with AD and 42 asymptomatic persons with a strong family history of AD. RESULTS: Forty-eight independent patients screened had a PS1 mutation including 21 novel mutations. In addition, 3% of subjects (11/413) had a known polymorphism, the Glu318Gly substitution. The majority of the mutations were missense substitutions but there were three insertions and Delta exon 10 mutation. With six exceptions (codons 35, 178, 352, 354, 358, and 365) most of the mutations occurred at residues conserved in the homologous PS2 gene or in PS1 of other species. CONCLUSIONS: Eleven percent of a referral-based series of patients with AD can be explained by coding sequence mutations in the PS1 gene. The high frequency of PS1 mutations in this study indicates that screening for PS1 mutations in AD is likely to be successful, especially when directed at patients with a positive family history with onset before 60 years (90% of those with PS1 mutations were affected by age 60 years). This will also have significance for the secondary identification of at-risk relatives who might be candidates for future prophylactic therapies for AD.
Assuntos
Doença de Alzheimer/genética , Testes Genéticos/métodos , Proteínas de Membrana/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Humanos , Pessoa de Meia-Idade , Presenilina-1 , Encaminhamento e Consulta , Análise de SobrevidaRESUMO
The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.
Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Cromossomos Humanos Par 14 , Genes fos/genética , Regiões Promotoras Genéticas/genética , Adulto , Ligação Genética , Humanos , Pessoa de Meia-Idade , Linhagem , Polimorfismo Genético , Mapeamento por RestriçãoRESUMO
To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Química Encefálica , Proteínas de Membrana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/análise , Precursor de Proteína beta-Amiloide/metabolismo , Ligação Genética , Humanos , Proteínas de Membrana/análise , Pessoa de Meia-Idade , Mutação Puntual , Presenilina-1 , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , SolubilidadeRESUMO
Mutation in the presenilin-1 (PS-1) gene at chromosome 14q24.3 is the most common cause of autosomal dominant early-onset Alzheimer's disease. Here, we report a novel missense mutation in the presenilin-1 gene found in a three-generation Danish family with autopsy-verified early-onset Alzheimer's disease. Two affected first-degree relatives in two generations were found to be heterozygous for a cytosine to adenine transversion at the second position of codon 116, which changes the amino acid at that position from threonine to asparagine. This conservative amino acid substitution occurs in an evolutionary highly conserved region of the PS-1 protein and is associated with onset of the disease between age 35 and 41 years and 4-8 years' duration of the disease. Analysis of amyloid beta-protein (A beta) deposition in brain specimens from one affected family member showed predominance of A beta 42(43). Onset and progression of the disease were very similar in two sibs homozygous for the epsilon 3 allele and the epsilon 4 allele, respectively, of the polymorphic apolipoprotein E locus. The lack of effect of the high risk epsilon 4/epsilon 4 genotype on the disease in this family corroborates and extends previous observations that the presence of one copy of the epsilon 4 allele does not modulate PS-1 associated Alzheimer's disease.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Substituição de Aminoácidos , Proteínas de Membrana/genética , Adulto , Idade de Início , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Encéfalo/metabolismo , Feminino , Genótipo , Humanos , Masculino , Mutação/genética , Linhagem , Fragmentos de Peptídeos/metabolismo , Presenilina-1RESUMO
The presenilin proteins are involved in the proteolytic processing of transmembrane proteins such as Notch/lin-12 and the beta-amyloid precursor protein (betaAPP). Mutation of a conserved cysteine (Cys60Ser) in the C. elegans presenilin sel-12 has a loss-of-function effect on Notch/lin-12 processing similar to that of null mutations in sel-12. In contrast, in mammalian cells, most missense mutations increase gamma-secretase cleavage of betaAPP. We report here that mutation of this conserved cysteine (Cys92Ser) in human presenilin 1 confers a loss-of-function effect in C. elegans, but causes increased A beta42 secretion in mammalian cells. These data suggest that the role of presenilins in Notch/lin-12 signalling and betaAPP processing are either separately regulated activities or independent activities of the presenilins.
Assuntos
Peptídeos beta-Amiloides/genética , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans/genética , Cisteína/genética , Proteínas de Helminto/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fragmentos de Peptídeos/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Helminto/genética , Humanos , Mutação de Sentido Incorreto/fisiologia , Fragmentos de Peptídeos/metabolismo , Mutação Puntual/genética , Presenilina-1 , Estrutura Terciária de Proteína/genética , Receptores Notch , Transdução de Sinais/genéticaRESUMO
The possibility of an interaction of multiple genes has been speculated in pathogenesis of Alzheimer's disease (AD). Because we have recently cloned a novel gene S182 bearing five different missense mutations which segregate with early-onset familial AD, we sought the frequency of these mutations in familial and sporadic late-onset AD to clarify the incidence of these mutations in the disease. The current study showed lack of these mutations in 118 independent subjects affected with late-onset Alzheimer's disease.