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1.
Hum Mutat ; 27(9): 888-96, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16917905

RESUMEN

Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutación Missense , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Bélgica , Encéfalo/diagnóstico por imagen , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Linaje , Tomografía de Emisión de Positrones , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Análisis de Secuencia de Proteína
2.
Neurobiol Aging ; 26(8): 1145-51, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15917097

RESUMEN

Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.


Asunto(s)
Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Quinasas Ciclina-Dependientes/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Anciano , Quinasa 5 Dependiente de la Ciclina , Análisis Mutacional de ADN , Exones/genética , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas , Variación Genética/genética , Genotipo , Haplotipos , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Países Bajos , Suecia
3.
Eur J Hum Genet ; 7(7): 801-6, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10573013

RESUMEN

Genetic association has been reported between a di-allelic polymorphism in intron 8 of presenilin-1 (PSEN1) and Alzheimer's disease (AD) in some studies but not in others. In a population-based series of 102 patients with early onset AD and 118 community controls we examined whether polymorphisms in linkage disequilibrium with intron8 of PSEN1 may explain the association. In addition to the intron 8 polymorphism (P = 0.05), a promoter polymorphism (P = 0.03) and the simple tandem repeat (STR) polymorphism D14S1028 located upstream of PSEN1 (P = 0.04) were found to be marginally significantly associated to AD. When excluding PSEN1 mutation cases (n = 6), the intron 8 association was explained by linkage disequilibrium to the dominant PSEN1 mutations. In the non-mutation cases, the weak associations between the polymorphisms in the regulatory region remained. Our study suggests that a polymorphism/mutation in the promoter or regulatory region of PSEN1 rather than the polymorphism in intron 8 of PSEN1 is associated with early onset AD.


Asunto(s)
Edad de Inicio , Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Anciano , Estudios de Casos y Controles , Genes Reguladores/genética , Humanos , Intrones/genética , Desequilibrio de Ligamiento , Persona de Mediana Edad , Mutación , Presenilina-1 , Secuencias Repetidas en Tándem/genética
4.
J Neurol ; 248(11): 935-9, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11757955

RESUMEN

We have previously reported a significant association between early-onset Alzheimer's disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimer's disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/biosíntesis , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Proteínas de la Membrana/análisis , Polimorfismo Genético , Presenilina-1 , Factores de Riesgo
5.
Neurosci Lett ; 199(1): 73-7, 1995 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-8584231

RESUMEN

Linkage analysis studies have indicated that the chromosome band 14q24.3 harbours a major gene for familial early-onset Alzheimer's disease (AD). Recently we localized the chromosome 14 AD gene (AD3) in the 6.4 cM interval between the markers D14S289 and D14S61. We mapped the gene encoding dihydrolipoyl succinyltransferase (DLST), the E2k component of human alpha-ketoglutarate dehydrogenase complex (KGDHC), in the AD3 candidate region using yeast artificial chromosomes (YACs). The DLST gene is a candidate for the AD3 gene since deficiencies in KGDHC activity have been observed in brain tissue and fibroblasts of AD patients. The 15 exons and the promoter region of the DLST gene were analysed for mutations in chromosome 14 linked AD cases and in two series of unrelated early-onset AD cases (onset age < 55 years). Sequence variations in intronic sequences (introns 3, 5 and 10) or silent mutations in exonic sequences (exons 8 and 14) were identified. However, no AD related mutations were observed, suggesting that the DLST gene is not the chromosome 14 AD3 gene.


Asunto(s)
Aciltransferasas/genética , Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 14/genética , Enfermedad de Alzheimer/enzimología , Secuencia de Bases , Mapeo Cromosómico , Exones , Ligamiento Genético , Humanos , Intrones , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Regiones Promotoras Genéticas
6.
SADJ ; 58(2): 48-53, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12800263

RESUMEN

BACKGROUND: Polymerisation shrinkage and the associated stress on composite resins and surrounding structures have been regarded as a major cause of leakage and clinical failures in modern polymer restorations. The purpose of this study was to investigate the effect of an additional flowable compomer layer on the microleakage of Class V dental cavities, which were further filled with a compomer. METHOD: Cavities (32) were prepared in human premolars, conditioned with a non-rinsing agent (Prime & Bond NRC) and treated with the bonding agent (Prime & Bond NT). Sixteen of these cavities were then lined with a layer of flowable compomer (Dyract Flow, approximately 0.5 mm) and further filled with Dyract AP. The other 16 cavities were filled without the flowable compomer. The specimens were thermo-cycled in a 0.5% basic fuchsin solution, sectioned and evaluated for dye penetration using a scoring system of 0 to 4. RESULTS: Lower microleakage values were found at the enamel as well as at the dentine sides when a layer of Dyract Flow was used as a liner. Furthermore, significantly (p < 0.05) lower microleakage was found in enamel than in dentine for both layered and unlayered restorations. CONCLUSION: It can be concluded that a layer of flowable compomer (i.e. Dyract Flow) in a cavity under a compomer may be recommended to improve the marginal seal of a restoration.


Asunto(s)
Compómeros , Recubrimiento de la Cavidad Dental , Filtración Dental/prevención & control , Restauración Dental Permanente/métodos , Diente Premolar , Preparación de la Cavidad Dental/métodos , Adaptación Marginal Dental , Humanos , Ácidos Polimetacrílicos
7.
Genes Brain Behav ; 7(2): 129-51, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17680806

RESUMEN

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.


Asunto(s)
Mitocondrias/genética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Apoptosis , Progresión de la Enfermedad , Enzimas/genética , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estrés Oxidativo , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/patología , Ubiquitina-Proteína Ligasas/genética
8.
Neurology ; 71(15): 1147-51, 2008 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-18838661

RESUMEN

BACKGROUND: Different loss-of-function mutations were identified underlying PGRN haploinsufficiency in patients with frontotemporal lobar degeneration. PGRN mutations were also identified in other neurodegenerative brain diseases such as amyotrophic lateral sclerosis and Alzheimer disease, though their biologic contribution to these diseases remains elusive. Because of its apparent role in neuronal survival, we argued that PGRN might also contribute to Parkinson disease (PD) pathogenesis. METHODS: We screened PGRN exons for mutations in 255 patients with PD and 459 control individuals by direct genomic sequencing. Genetic association of PGRN with risk for PD was assessed using single nucleotide polymorphisms (SNPs) across the gene. RESULTS: In patients we identified four missense mutations of which p.Asp33Glu and p.Arg514Met were absent in control individuals. Single SNP and haplotype analyses did not detect significant associations with PD. CONCLUSIONS: Our results do not support a major role for PGRN in the genetic etiology of Parkinson disease (PD). At this stage and in the absence of functional data, it remains unclear whether p.Asp33Glu and p.Arg514Met are biologically relevant to PD pathogenesis in the mutation carriers.


Asunto(s)
Variación Genética , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación Missense , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Anciano , Secuencia de Aminoácidos , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Enfermedad de Parkinson/epidemiología , Progranulinas , Estudios Retrospectivos , Factores de Riesgo
9.
Neurology ; 70(16 Pt 2): 1456-60, 2008 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-18337586

RESUMEN

OBJECTIVE: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C. METHODS: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. RESULTS: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation. CONCLUSIONS: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.


Asunto(s)
Sustitución de Aminoácidos/genética , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/fisiopatología , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Arginina/genética , Cisteína/genética , Análisis Mutacional de ADN , Femenino , Glicina/genética , Haplotipos/genética , Humanos , Internacionalidad , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Serina/genética
10.
Hum Mol Genet ; 9(16): 2383-94, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11005793

RESUMEN

In recent years, important progress has been made in uncovering genes implicated in Alzheimer's disease (AD). Three causal genes have been identified in which mutations cause familial presenile AD: the amyloid precursor protein gene and the presenilin 1 and 2 genes. Additionally, the epsilon 4 allele of the apolipoprotein E gene was shown to be a major risk factor for AD. Despite the genetic heterogeneity, all of these genes work through a common mechanism, i. e. increasing the amount and deposition of the amyloid beta peptide (A beta) in brain triggering AD-related neuronal degeneration. Therefore, the levels of A beta and of the factors involved in its production and deposition are important in the neuropathogenesis of AD. Regulation of transcription of AD genes might therefore be an important player in the neurodegenerative process. In this review, we describe the major features of transcriptional regulation of the known AD genes and the implications of variable expression levels on susceptibility to AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Regulación de la Expresión Génica , Animales , Secuencia de Bases , ADN , Predisposición Genética a la Enfermedad , Humanos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Transcripción Genética
11.
Acta Neuropsychiatr ; 11(2): 60-2, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26976255

RESUMEN

Alzheimer disease (AD), the most common form of dementia in the elderly, is rapidly becoming a major health problem in developed countries where the number of elderly people continuously grows due to improved medical care. Consequently, the number of AD patients is increasing and thus far no effective therapies are available. Clinically the disease can be diagnosed with 90% reliability on the basis of neurological examination, neuropsychological testing and brain imaging techniques. A definite diagnosis, however, requires the post-mortem detection of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. The SPs are extracellular deposits mainly composed of amyloid P (Ap) surrounded by dystrophic neurites. NFT are intraneural inclusions of paired helical filaments composed of hyperphosphorylated tau. Although age is the major risk factor for AD, population survey and family studies have provided substantial evidence that genetic factors are major contributors to the expression of AD.

12.
Hum Mol Genet ; 4(8): 1355-64, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7581374

RESUMEN

Genetic linkage studies have provided significant evidence that a major gene defect, AD3, for familial early-onset Alzheimer's disease (EOAD) is located at chromosome 14q24.3, between the short tandem repeat (STR) markers D14S52 and D14S53 defining a genetic size of 22.7 cM for the AD3 candidate region. We constructed a physical map of the AD3 region using yeast artificial chromosomes (YACs) selected from both the CEPH and megaCEPH YAC libraries using the AD3 linked STR markers as well as new sequence-tagged sites (STSs) designed based on YAC terminal sequences. The YAC map is contiguous in the region between D14S258 and D14S53, a region of 8.2 cM, and has an estimated physical size of 4-8 Mb. The YAC contig map was used as a framework to localize three known genes, a pseudogene and two brain expressed sequence tags (ESTs). Linkage analysis studies in two Belgian chromosome 14 EOAD families AD/A and AD/B, identified obligate recombinants in family AD/A with D14S289 and D14S61 reducing the genetic size of the candidate AD3 region substantially. The minimal AD3 candidate region measured 6.4 cM on the genetic map and is contained within six overlapping megaCEPH YACs that covered a physical distance estimated between 2 and 6 Mb. These YACs as well as other YACs in the YAC contig map are valuable resources in gene cloning efforts or genomic sequencing experiments aiming at isolating the AD3 gene.


Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 14/genética , Edad de Inicio , Anciano , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Artificiales de Levadura/genética , Clonación Molecular , Cartilla de ADN/genética , Femenino , Biblioteca de Genes , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Lugares Marcados de Secuencia
13.
J Neurol Neurosurg Psychiatry ; 75(8): 1166-70, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15258222

RESUMEN

OBJECTIVES: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. METHODS: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. RESULTS: We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. CONCLUSIONS: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.


Asunto(s)
Demencia/genética , Demencia/patología , Priones/genética , Secuencias Repetitivas de Ácidos Nucleicos , Edad de Inicio , Progresión de la Enfermedad , Humanos , Fenotipo , Análisis de Regresión , Factores de Tiempo
14.
Brain ; 127(Pt 7): 1641-9, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15130954

RESUMEN

Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.


Asunto(s)
Demencia/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Análisis por Conglomerados , Consanguinidad , Demencia/epidemiología , Demencia Vascular/genética , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/genética , Escala de Lod , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Oportunidad Relativa , Linaje , Medición de Riesgo , alfa-Macroglobulinas/genética
15.
Hum Mol Genet ; 9(3): 325-31, 2000 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-10655540

RESUMEN

Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to the 5' regulatory region of PSEN1. In this study we systematically screened 3.5 kb of the PSEN1 upstream region and found four novel polymorphisms. Genetic analysis confirmed association of two polymorphisms with increased risk for EOAD. In addition, we detected two different mutations in EOAD cases at-280 and-2818 relative to the transcription initiation site in exon 1A of PSEN1. Analysis of the mutant and wild-type-280 variants using luciferase reporter gene expression in transiently transfected neuroblastoma cells showed a 30% decrease in transcriptional activity for the mutant-280G PSEN1 promoter variant compared with the wild-type variant-280C. Our data suggest that the increased risk for EOAD associated with PSEN1 may result from genetic variations in the regulatory region leading to altered expression levels of the PSEN1 protein.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Secuencias Reguladoras de Ácidos Nucleicos , Anciano , Animales , Línea Celular , ADN/sangre , Análisis Mutacional de ADN , Femenino , Genes Reporteros , Variación Genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , Presenilina-1 , Mapeo Restrictivo , Factores de Riesgo , Transfección
16.
Hum Mol Genet ; 4(12): 2363-71, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8634711

RESUMEN

Genetic linkage studies have indicated that chromosome 14q24.3 harbours a major locus for early-onset (onset age <65 years) Alzheimer's disease (AD3). Positional cloning efforts have identified a novel gene S182 or presenilin 1 as the AD3 gene. We have mapped S182 in the AD3 candidate region between D14S277 and D14S284 defined by genetic linkage studies in the two chromosome 14 linked, early-onset AD families AD/A and AD/B. We have shown that S182 is expressed in lymphoblasts and have determined the complete cDNA in both brain and lymphoblasts by RT-PCR sequencing. S182 is alternatively spliced in both brain and lymphoblasts within a putative phosphorylation site located 5' in the coding region. We identified two novel mutations, Ile143Thr and Gly384la located in, respectively, the second transmembrane domain and in the sixth hydrophilic loop of the putative transmembrane structure of S182. As families AD/A and AD/B have very similar AD phenotype our observation of two mutations in functionally different domains suggest that onset age and severity of AD may not be very helpful predictors of the location of putative S182 mutations.


Asunto(s)
Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 14 , Proteínas de la Membrana/genética , Edad de Inicio , Secuencia de Bases , Cromosomas Artificiales de Levadura , ADN Complementario , Femenino , Ligamiento Genético , Humanos , Desequilibrio de Ligamiento , Masculino , Datos de Secuencia Molecular , Mutación , Linaje , Presenilina-1
17.
Hum Mol Genet ; 7(2): 177-86, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9425224

RESUMEN

Autosomal dominant cerebellar ataxia with retinal degeneration (ADCAII) was previously mapped by linkage analysis studies to chromosome 3p12-p21.1 (SCA7). Positional cloning efforts have recently identified a novel gene, SCA7 , containing a translated CAG repeat, expanded in SCA7 patients. We cloned the SCA7 gene from a yeast artificial chromosome (YAC) clone contig spanning the SCA7 candidate region. Using a combination of genomic sequencing and cosmid-based exon trapping, two expressed sequence tags were identified. Sequencing of the corresponding cDNA clones and RT-PCR analysis identified the full-length SCA7 cDNA. Together, our sequence data defined the intron/exon boundaries of the first two coding exons of the SCA7 gene, with the first exon containing the expanded CAG repeat. Further, sequence comparison with the published SCA7 cDNA identified one additional putative exon in the 5'-UTR region of the SCA7 gene. The SCA7 gene was mapped on the YAC contig in the 2.5 cM interval between D3S1600 and D3S1287. In one extended Belgian SCA7 pedigree the expanded alleles ranged from 38 to at least 55 repeats with allele lengths being inversely correlated with onset age of ADCAII symptoms. The SCA7 repeats increased in length in successive generations. Normal alleles had from four to 18 repeats, with 10 repeats being the most common allele.


Asunto(s)
Cromosomas Humanos Par 3/genética , Degeneración Macular/genética , Degeneraciones Espinocerebelosas/genética , Repeticiones de Trinucleótidos , Alelos , Secuencia de Bases , Bélgica/epidemiología , Cromosomas Artificiales de Levadura , Clonación Molecular , Cósmidos , ADN Complementario/genética , Femenino , Expresión Génica , Humanos , Degeneración Macular/clasificación , Degeneración Macular/epidemiología , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Degeneraciones Espinocerebelosas/clasificación , Degeneraciones Espinocerebelosas/epidemiología
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