RESUMEN
Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas de Transporte de Membrana/genética , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/veterinaria , Animales , Perros , Femenino , Masculino , Lipofuscinosis Ceroideas Neuronales/patología , Reacción en Cadena de la Polimerasa , Tripeptidil Peptidasa 1RESUMEN
Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.
Asunto(s)
Ganglios Basales/patología , Cerebelo/patología , Distonía Muscular Deformante/genética , Pleiotropía Genética , Leucoencefalopatías/genética , Tubulina (Proteína)/genética , Trastornos de la Voz/congénito , Adulto , Distonía Muscular Deformante/patología , Distonía Muscular Deformante/fisiopatología , Exones , Femenino , Heterocigoto , Humanos , Leucoencefalopatías/patología , Leucoencefalopatías/fisiopatología , Masculino , Mutación , Fenotipo , Trastornos de la Voz/genética , Trastornos de la Voz/patología , Trastornos de la Voz/fisiopatologíaRESUMEN
Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/genética , Trastornos Parkinsonianos/genética , ATPasas de Translocación de Protón/genética , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Exoma/genética , Salud de la Familia , Femenino , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Lipofuscinosis Ceroideas Neuronales/patología , Linaje , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD). METHODS: We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD). RESULTS: We confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P = .03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from "typical" sporadic AD. CONCLUSION: We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Arginina/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Histidina/genética , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Encéfalo/patología , Estudios de Cohortes , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patología , Exones/genética , Femenino , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Factores de RiesgoRESUMEN
In the present review, we look back at the recent history of GWAS (genome-wide association studies) in AD (Alzheimer's disease) and integrate the major findings with current knowledge of biological processes and pathways. These topics are essential for the development of animal models, which will be fundamental to our complete understanding of AD.
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Enfermedad de Alzheimer/genética , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/metabolismo , Animales , Proteínas del Sistema Complemento/genética , Endocitosis/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Inflamación/complicaciones , Inflamación/genética , Metabolismo de los Lípidos/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Mutations in APP, PSEN1, MAPTand GRNare the most common genetic causes of dementia. The previous miss-assignment of pathogenicity to benign variants in these genes stresses the importance of discerning between disease causing mutations and benign variants with no pathogenic effect on the function of the respective protein. In this study we sequenced GRNand MAPTin 282 samples from the Centre d'Etude du Polymorphisme Humain - Human Genome Diversity Cell Line Panel, in order to identify benign variants that could otherwise be mistaken for pathogenic mutations. We found sixteen different non-synonymous changes, eleven of which are novel variants.
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Variación Genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas tau/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Exones/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Datos de Secuencia Molecular , Sistemas de Lectura Abierta/genética , Progranulinas , Estructura Terciaria de Proteína , Alineación de Secuencia , Proteínas tau/químicaRESUMEN
OBJECTIVE: To describe a dementia case clinically diagnosed as Alzheimer disease with a PRNP genotype usually associated with familial fatal insomnia. METHODS: Polymerase chain reaction amplification and subsequent direct sequencing of PGRN, MAPT, PSEN1, PSEN2, APP, and PRNP genes. RESULTS: A point mutation (D178N) was found in the PRNP gene. CONCLUSIONS: The mutation D178N in the PRNP gene associated with the M129 genotype is usually associated with familial fatal insomnia. However, a few cases have been reported with different clinical phenotypes. Here, we describe one of these cases and stress the importance of genetic screening of PRNP in early onset dementia cases.
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Demencia/diagnóstico , Demencia/genética , Insomnio Familiar Fatal , Priones/genética , Asparagina/genética , Ácido Aspártico/genética , Femenino , Genotipo , Humanos , Insomnio Familiar Fatal/diagnóstico , Insomnio Familiar Fatal/genética , Persona de Mediana Edad , Mutación Puntual , Proteínas PriónicasRESUMEN
Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aß in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aß peptides. We report that soluble oligomers were specifically detected in the dog's blood and cerebrospinal fluid (CSF) via anti-oligomer- and anti-Aß specific binders. Importantly, our results reveal the potent neurotoxic effects of the dog's CSF on cell viability and the seeding efficiency of the CSF-borne soluble oligomers on the thermodynamic activity and the aggregation kinetics of synthetic human Aß. The value of further characterizing the naturally occurring Alzheimer-like neuropathology in dogs using genetic and molecular tools is discussed.
RESUMEN
BACKGROUND: The presence of deletions can complicate genetic diagnosis of autosomal recessive disease. METHOD: The DNA of patients was analyzed in a diagnostic setting. RESULTS: We present three unrelated patients each carrying deletions that encompass the 37 kb CLN8 gene and discuss their phenotype. Two of the cases were hemizygous for a mutant allele - their deletions unmasked a mutation in CLN8 on the other chromosome. CONCLUSION: Microarray analysis is recommended in any patient suspected of NCL who is apparently homozygous for a mutation that is not present in one of the parents or when the family has no known consanguinity.
RESUMEN
BACKGROUND: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. METHODS: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. RESULTS: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. CONCLUSION: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.
Asunto(s)
Enfermedad de Alzheimer/genética , Trastornos del Conocimiento/genética , Predisposición Genética a la Enfermedad/genética , Antígenos de Histocompatibilidad Clase I/genética , Trastornos del Metabolismo del Hierro/genética , Proteínas de la Membrana/genética , Enfermedad de Parkinson/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/fisiopatología , Estudios de Cohortes , Comorbilidad , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas , Variación Genética/genética , Genotipo , Proteína de la Hemocromatosis , Humanos , Hierro/metabolismo , Trastornos del Metabolismo del Hierro/epidemiología , Trastornos del Metabolismo del Hierro/fisiopatología , Masculino , Persona de Mediana Edad , Mutación/genética , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/fisiopatología , Portugal/epidemiología , Tamaño de la Muestra , Distribución por SexoRESUMEN
OBJECTIVE: To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder. METHODS: Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease. RESULTS: All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del). CONCLUSIONS: This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.
RESUMEN
We describe a sporadic case of atypical parkinsonism-dystonia of subacute onset at the age of 16 years in a male from a consanguineous family. He showed marked orofacial dystonia, levodopa-induced dyskinesia, and a stereotyped bilateral eye-pressing movement disorder. We combined Sanger sequencing of candidate genes, homozygosity mapping, and whole-exome sequencing. A homozygous mutation was identified disrupting a splice site in exon 5 of the DJ1 (PARK7) gene. Clinical details and a video are provided. DJ1 mutations are a rare cause of atypical complex parkinsonism. Exome sequencing is efficacious in identifying the causal gene variant.
RESUMEN
Alzheimer's disease (AD) is a complex disorder with a clear genetic component. Three genes have been identified as the cause of early onset familial AD (EOAD). The most common form of the disease, late onset Alzheimer's disease (LOAD), is, however, a sporadic one presenting itself in later stages of life. The genetic component of this late onset form of AD has been the target of a large number of studies, because only one genetic risk factor (APOE4) has been consistently associated with the disease. However, technological advances allow new approaches in the study of complex disorders. In this review, we discuss the new results produced by genome wide association studies, in light of the current knowledge of the complexity of AD genetics.
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteínas E/genética , Presenilina-1/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/genética , Animales , Apolipoproteínas E/biosíntesis , Apolipoproteínas E/química , Humanos , Presenilina-1/biosíntesis , Presenilina-1/química , Presenilina-2/biosíntesis , Presenilina-2/química , Presenilina-2/genéticaRESUMEN
In order to assess the frequency of mutations in the known Alzheimer's disease causative genes in Turkish dementia patients we screened amyloid precursor protein (APP), PSEN1 and PSEN2 for mutations in a cohort of 98 Turkish dementia families. Six families were found to carry PSEN1 mutations (p.H163R, p.P264L, and p.H214Y) or variants suggested to cause the disease (p.L134R, p.L262V, and p.A396T). In 4 other families, previously reported PSEN2 variants were identified (p.R62H, p.R71W, p.M174V (n = 2), and p.S130L). The phenotype of the carriers varied from rapid progressing Alzheimer's disease to frontotemporal dementia, with spasticity and seizures also observed. Here we report a frequency of 11.2% of mutations and variants in the known Alzheimer disease genes in the dementia cohort studied and 24% in the early onset subgroup of patients, suggesting that mutations in these genes are not uncommon in Turkey and are associated with various phenotypes. We thus believe that genetic analysis should become a standardized diagnostic implement, not only for the identification of the genetic disease, but also for appropriate genetic counseling.
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Demencia/epidemiología , Demencia/genética , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Polimorfismo de Nucleótido Simple/genética , Presenilina-1/genética , Anciano , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Turquía/epidemiologíaRESUMEN
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Cromosomas Humanos Par 9 , Demencia Frontotemporal/genética , Repeticiones de Microsatélite , Alelos , Femenino , Finlandia , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU. METHODOLOGY/PRINCIPAL FINDINGS: To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD. CONCLUSIONS/SIGNIFICANCE: We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.
Asunto(s)
Enfermedad de Alzheimer/genética , Clusterina/genética , Regulación de la Expresión Génica , Variación Genética , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Clusterina/fisiología , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: TAR DNA binding protein, encoded by TARDBP, was shown to be a central component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, mutations in TARDBP have been linked to familial and sporadic ALS. METHODOLOGY/PRINCIPAL FINDINGS: To further examine the frequency of mutations in TARDBP in sporadic ALS, 279 ALS cases and 806 neurologically normal control individuals of European descent were screened for sequence variants, copy number variants, genetic and haplotype association with disease. An additional 173 African samples from the Human Gene Diversity Panel were sequenced as this population had the highest likelihood of finding changes. No mutations were found in the ALS cases. Several genetic variants were identified in controls, which were considered as non-pathogenic changes. Furthermore, pathogenic structural variants were not observed in the cases and there was no genetic or haplotype association with disease status across the TARDBP locus. CONCLUSIONS: Our data indicate that genetic variation in TARDBP is not a common cause of sporadic ALS in North American.