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
We report on a pair of siblings with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and a novel Thr462Lysfs mutation in the TANK-binding kinase 1 (TBK1) gene identified through the European Early-Onset Dementia Consortium. The patients presented at the age of 77 and 75 years and displayed dementia and bulbar symptoms as well as progressive paresis. After a progressive course, both of them died only a few months after diagnosis. Most recently, TBK1 mutations were identified in patients with FTD and ALS.âA loss of expression of the mutant allele, leading to 50â% reduced TBK1 protein levels, seems to be causative. The occurrence of TBK1 mutations in FTD and ALS underlines the fact that FTD and ALS are part of the same disease spectrum. For future therapeutic trials, characterization of TBK1 mutation carriers in presymptomatic cohorts, such as the genetic frontotemporal dementia initiative (GENFI), is of great importance.
Assuntos
Alelos , Esclerose Lateral Amiotrófica/genética , Análise Mutacional de DNA , Demência Frontotemporal/genética , Irmãos , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Encéfalo/patologia , Comorbidade , Progressão da Doença , Feminino , Demência Frontotemporal/diagnóstico , Testes Genéticos , Humanos , Imageamento por Ressonância Magnética , Masculino , Exame Neurológico , Linhagem , Tomografia por Emissão de PósitronsRESUMO
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele â¼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteínas tau/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Endofenótipos , Expressão Gênica/genética , Humanos , Camundongos , Degeneração Neural/genética , Degeneração Neural/patologia , Proteínas Nucleares/biossíntese , Placa Amiloide/patologia , Polimorfismo de Nucleotídeo Único/genética , Sinaptossomos/patologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Proteínas tau/antagonistas & inibidoresRESUMO
Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) É4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1â42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.
Assuntos
Doença de Alzheimer/genética , Fator I do Complemento/metabolismo , Variações do Número de Cópias de DNA/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Complemento/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Estudos de Coortes , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Metanálise como Assunto , Razão de Chances , Fragmentos de Peptídeos/líquido cefalorraquidiano , Duplicações Segmentares Genômicas , Proteínas tau/líquido cefalorraquidianoRESUMO
Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase gamma (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.
Assuntos
DNA Mitocondrial/genética , DNA Polimerase Dirigida por DNA/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Bélgica , Cromossomos Humanos Par 15/genética , DNA Polimerase gama , Feminino , Heterozigoto , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Mutação , Mutação de Sentido Incorreto , Oftalmoplegia Externa Progressiva Crônica/enzimologia , Oftalmoplegia Externa Progressiva Crônica/epidemiologia , Linhagem , Deleção de Sequência , Homologia de Sequência de AminoácidosRESUMO
Genetic linkage studies with chromosome 21 DNA markers and mutation analysis of the beta-amyloid protein precursor gene located in 21q21.3 have indicated that early-onset Alzheimer's disease (EOAD) is a heterogeneous disorder for which at least one other chromosomal locus exists. We examined two extended histopathologically confirmed EOAD pedigrees, AD/A and AD/B, with highly informative short tandem repeat (STR) polymorphisms and found complete linkage of the disease to a (CA)n dinucleotide repeat polymorphism at locus D14S43 in 14q24.3 (Zmax = 13.25 at theta = 0.0). Using additional chromosome 14 STR polymorphisms we were able to delineate the region containing the EOAD gene to an area of, at most, 8.9 centiMorgans between D14S42 and D14S53, flanking D14S43 on both sides.
Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14 , Adulto , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 21 , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Linhagem , Polimorfismo Genético , Sequências Repetitivas de Ácido NucleicoRESUMO
Several studies have reported an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (LOAD). Here we report on the relationship between APOE*4 and early-onset Alzheimer's disease (EOAD) in a Dutch population-based study. The frequency of the APOE*4 allele was 2.3 times higher among EOAD cases compared to controls. Among patients, the allele frequency was 1.6 times higher in those with a positive family history than in those without. A significant increase in risk of EOAD was found for subjects homozygous for APOE*4 regardless of family history of dementia, but an increase in EOAD risk for APOE*4 heterozygotes could only be shown in subjects with a positive family history. Our study demonstrates a significant association between APOE*4 and EOAD which is modified by family history of dementia.
Assuntos
Alelos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Adulto , Idade de Início , Idoso , Doença de Alzheimer/epidemiologia , Apolipoproteína E4 , Saúde da Família , Feminino , Frequência do Gene , Genes Dominantes , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Predisposição Genética para Doença/genética , Hereditariedade/genética , Fatores Etários , Idoso , Alelos , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Feminino , França/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. CONCLUSION: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.
Assuntos
Técnicas de Diagnóstico Molecular , Doença dos Neurônios Motores/diagnóstico , Doenças Musculares/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Humanos , Doença dos Neurônios Motores/genética , Doenças Musculares/genética , Doenças do Sistema Nervoso Periférico/genéticaRESUMO
OBJECTIVES: These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders. CONCLUSION: These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.
Assuntos
Canalopatias/diagnóstico , Demência/diagnóstico , Epilepsia/diagnóstico , Transtornos de Enxaqueca/diagnóstico , Biologia Molecular/normas , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Acidente Vascular Cerebral/diagnóstico , Canalopatias/epidemiologia , Canalopatias/genética , Demência/epidemiologia , Demência/genética , Epilepsia/epidemiologia , Epilepsia/genética , Europa (Continente)/epidemiologia , Medicina Baseada em Evidências , Humanos , Recém-Nascido , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/genética , Biologia Molecular/métodos , Biologia Molecular/tendências , Técnicas de Diagnóstico Molecular/tendências , Sociedades Médicas/normas , Sociedades Médicas/tendências , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.
Assuntos
Ataxia/diagnóstico , Ataxia/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Ataxia/metabolismo , Humanos , Paraplegia/diagnóstico , Paraplegia/genética , Paraplegia/metabolismo , Paraplegia Espástica Hereditária/metabolismoRESUMO
We report the results of a 10 cM density genome-wide scan and further fine mapping of three chromosomal candidate regions in 10 Belgian multigenerational families with bipolar (BP) disorder. This two-stage approach revealed significant evidence for linkage on chromosome 10q21.3-10q22.3, showing a maximum multipoint parametric heterogeneity logarithm of odds (HLOD) score of 3.28 and a nonparametric linkage (NPL) score of 4.00. Most of the chromosome 10q evidence was derived from a single, large Ashkenazi Jewish pedigree. Haplotype analysis in this pedigree shows that the patients share a 14-marker haplotype, defining a chromosomal candidate region of 19.2 cM. This region was reported previously as a candidate region for BP disorder in several independent linkage analysis studies and in one large meta-analysis. It was also implicated in a linkage study on schizophrenia (SZ) in Ashkenazi Jewish families. Additionally, we found suggestive evidence for linkage on chromosome 19q13.2-13.4 (HLOD 2.01, NPL 1.09) and chromosome 7q21-q22 (HLOD 1.45, NPL 2.28). Together, these observations suggest that a gene located on chromosome 10q21.3-10q22.3 is underlying the susceptibility both for SZ and for BP disorder in at least the Ashkenazi Jewish population.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 10 , Saúde da Família , Predisposição Genética para Doença , Adulto , Mapeamento Cromossômico/métodos , Feminino , Ligação Genética , Genótipo , Humanos , Judeus , Escore Lod , Masculino , Razão de ChancesRESUMO
Human hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), an autosomal dominant form of cerebral amyloid angiopathy (CAA), is characterized by extensive amyloid deposition in the small leptomeningeal arteries and cortical arterioles, which lead to an early death of those afflicted in their fifth or sixth decade. Immunohistochemical and biochemical studies have indicated that the amyloid subunit in HCHWA-D is antigenically related to and homologous in sequence with the amyloid beta protein isolated from brains of patients with Alzheimer's disease and Down syndrome. The amyloid beta protein is encoded by the amyloid beta protein precursor (APP) gene located on chromosome 21. Restriction fragment length polymorphisms detected by the APP gene were used to examine whether this gene is a candidate for the genetic defect in HCHWA-D. The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCHWA-D.
Assuntos
Amiloide/genética , Amiloidose/genética , Hemorragia Cerebral/genética , Transtornos Cerebrovasculares/genética , Precursores de Proteínas/genética , Adulto , Idoso , Precursor de Proteína beta-Amiloide , Amiloidose/complicações , Hemorragia Cerebral/etiologia , Transtornos Cerebrovasculares/complicações , Feminino , Genes Dominantes , Ligação Genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Países Baixos , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
We report a unique case with co-occurrence of Turner syndrome and Fabry disease (OMIM #301500). The latter is a rare X-linked lysosomal storage disease that is characterized by partial or complete deficiency of alpha-galactosidase A (GLA; EC 3.2.1.22) following mutations in the gene (GLA) localized at Xq22.1. Accumulation of metabolic intermediates can occur in many tissues and leads to severe morbidity, especially due to renal failure, cardiac involvement and stroke. It is well established that hemizygous male mutation carriers with Fabry disease are generally more severely affected than heterozygous female mutation carriers, but disabling clinical features and disease progression often occur in female Fabry patients as well. The majority of this patient's cells are of the 45,X type, making her a hemizygous GLA mutation carrier displaying a very severe Fabry disease phenotype.
Assuntos
Doença de Fabry/complicações , Doença de Fabry/genética , Síndrome de Turner/complicações , Síndrome de Turner/genética , alfa-Galactosidase/genética , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/patologia , Cromossomos Humanos X/genética , Análise Mutacional de DNA , Éxons , Doença de Fabry/enzimologia , Doença de Fabry/patologia , Feminino , Hemizigoto , Humanos , Cariótipo , Masculino , Mosaicismo , Mutação de Sentido Incorreto , Fenótipo , Pele/patologia , Adulto Jovem , alfa-Galactosidase/sangueRESUMO
OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.
Assuntos
Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Biologia Molecular/métodos , HumanosRESUMO
BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.
Assuntos
Distonia/diagnóstico , Guias como Assunto/normas , Doença de Huntington/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Doença de Parkinson/diagnóstico , Bases de Dados Bibliográficas/estatística & dados numéricos , Distonia/genética , Aconselhamento Genético/métodos , Humanos , Doença de Huntington/genética , Doença de Parkinson/genéticaRESUMO
Hereditary demyelinating peripheral neuropathies consist of a heterogeneous group of genetic disorders that includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas syndrome (DSS), and congenital hypomyelination (CH). The clinical classification of these neuropathies into discrete categories can sometimes be difficult because there can be both clinical and pathologic variation and overlap between these disorders. We have identified five novel mutations in the myelin protein zero (MPZ) gene, encoding the major structural protein (P0) of peripheral nerve myelin, in patients with either CMT1B, DSS, or CH. This finding suggests that these disorders may not be distinct pathophysiologic entities, but rather represent a spectrum of related "myelinopathies" due to an underlying defect in myelination. Furthermore, we hypothesize the differences in clinical severity seen with mutations in MPZ are related to the type of mutation and its subsequent effect on protein function (i.e., loss of function versus dominant negative).
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/genética , Neuropatia Hereditária Motora e Sensorial/genética , Proteína P0 da Mielina/genética , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico , Clonagem Molecular , Estudos de Coortes , Cristalografia , Análise Mutacional de DNA , Doenças Desmielinizantes/congênito , Doenças Desmielinizantes/diagnóstico , Feminino , Genótipo , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Humanos , Masculino , Microscopia Eletrônica , Proteína P0 da Mielina/química , Fenótipo , Mutação Puntual/fisiologia , Conformação Proteica , Nervo Sural/ultraestruturaRESUMO
Mutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified.
Assuntos
Demência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Família , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Doenças Neurodegenerativas/genética , ProgranulinasRESUMO
Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.