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1.
Neurogenetics ; 13(1): 97-101, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22294494

RESUMO

Investigations into migraine genetics have suggested that susceptibility loci exist on the X chromosome. These reports are supported by evidence that demonstrates male probands as having a higher proportion of affected first-degree relatives as well as the female preponderance of 3:1 that the disorder displays. We have previously implicated the Xq24-28 locus in migraine using two independent multigenerational Australian pedigrees that demonstrated excess allele sharing at the Xq24, Xq27 and Xq28 loci. Here, we expand this work to investigate a further six independent migraine pedigrees using 11 microsatellite markers spanning the Xq27­28 region. Furthermore, 11 candidate genes are investigated in an Australian case-control cohort consisting of 500 cases and 500 controls. Microsatellite analysis showed evidence of excess allele sharing to the Xq27 marker DXS8043 (LOD* 1.38 P00.005) in MF879 whilst a second independent pedigree showed excess allele sharing to DXS8061 at Xq28 (LOD* 1.5 P00.004). Furthermore, analysis of these key markers in a case control cohort showed significant association to migraine in females at the DXS8043 marker (T1 P00.009) and association with MO at DXS8061 (T1 P00.05). Further analysis of 11 key genes across these regions showed significant association of a three-marker risk haplotype in the NSDHL gene at Xq28 (P00.0082). The results of this study add further support to the presence of migraine susceptibility loci on chromosome Xq27 and Xq28 as well as point to potential candidate genes in the regions that warrant further investigation.


Assuntos
Cromossomos Humanos X/genética , Predisposição Genética para Doença , Transtornos de Enxaqueca/genética , Austrália , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Linhagem , Polimorfismo de Nucleotídeo Único
2.
Brain Res ; 1378: 119-24, 2011 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-21195698

RESUMO

Migraine is a neurological disorder that is associated with increased levels of calcitonin gene-related peptide (CGRP) in plasma. CGRP, being one of the mediators of neurogenic inflammation and a phenomenon implicated in the pathogenesis of migraine headache, is thus suggested to have an important role in migraine pathophysiology. Polymorphisms of the CALCA gene have been linked to Parkinson's disease, ovarian cancer and essential hypertension, suggesting a functional role for these polymorphisms. Given the strong evidence linking CGRP and migraine, it is hypothesised that polymorphisms in the CALCA gene may play a role in migraine pathogenesis. Seemingly non functional intronic polymorphisms are capable of disrupting normal RNA processing or introducing a splice site in the transcript. A 16bp deletion in the first intron of the CALCA gene has been reported to be a good match for the binding site for a transcription factor expressed strongly in neural crest derived cells, AP-2. This deletion also eliminates an intron splicing enhancer (ISE) that may potentially cause exon skipping. This study investigated the role of the 16bp intronic deletion in the CALCA gene in migraineurs and matched control individuals. Six hundred individuals were genotyped for the deletion by polymerase chain reaction followed by fragment analysis on the 3130 Genetic Analyser. The results of this study showed no significant association between the intronic 16bp deletion in the CALCA gene and migraine in the tested Australian Caucasian population. However, given the evidence linking CGRP and migraine, further investigation of variants with this gene may be warranted.


Assuntos
Calcitonina/genética , Predisposição Genética para Doença/genética , Transtornos de Enxaqueca/genética , Polimorfismo Genético , Precursores de Proteínas/genética , Austrália , Peptídeo Relacionado com Gene de Calcitonina , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Reação em Cadeia da Polimerase
3.
Cephalalgia ; 31(3): 264-70, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20813781

RESUMO

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) shares common symptoms with migraine. Most CADASIL causative mutations occur in exons 3 and 4 of the Notch 3 gene. This study investigated the role of C381T (rs 3815188) and G684A (rs 1043994) single nucleotide polymorphisms (SNP) in exons 3 and 4, respectively, of the Notch 3 gene in migraine. RESULTS: The first part of the study, in a population of 275 migraineurs and 275 control individuals, found a significant association between the C381T variant and migraine, specifically in migraine without aura (MO) sufferers. The G684A variant was also found to be significantly associated with migraine, specifically in migraine with aura (MA) sufferers. A follow-up study in 300 migraineurs and 300 control individuals did not show replicated association of the C381T variant with migraineurs. However, the G684A variant was again shown to be significantly associated with migraine, specifically with MA. CONCLUSION: Further investigation of the G684A variant and the Notch 3 gene is warranted to understand their role in migraine.


Assuntos
Predisposição Genética para Doença , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Receptores Notch/genética , Genótipo , Humanos , Reação em Cadeia da Polimerase , Receptor Notch3
4.
Cell Mol Biol (Noisy-le-grand) ; 51(3): 285-92, 2005 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-16191396

RESUMO

The ubiquitous chemical messenger molecule nitric oxide (NO) has been implicated in a diverse range of biological activities including neurotransmission, smooth muscle motility and mediation of nociception. Endogenous synthesis of NO by the neuronal isoform of the nitric oxide synthase gene family has an essential role within the central and peripheral nervous systems in addition to the autonomic innervation of cerebral blood vessels. To investigate the potential role of NO and more specifically the neuronal nitric oxide synthase (nNOS) gene in migraine susceptibility, we investigated two microsatellite repeat variants residing within the 5' and 3' regions of the nNOS gene. Population genomic evaluation of the two nNOS repeat variants indicated significant linkage disequilibrium between the two loci. Z-DNA conformational sequence structures within the 5' region of the nNOS gene have the potential to enhance or repress gene promoter activity. We suggest that genetic analysis of this 5' repeat variant is the more functional variant expressing gene wide information that could affect endogenous NO synthesis and potentially result in diseased states. However, no association with migraine (with or without aura) was seen in our extensive case-control cohort (n = 579 affected with matched controls), when both the 5' and 3' genetic variants were investigated.


Assuntos
Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Repetições de Microssatélites , Transtornos de Enxaqueca/genética , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Região 3'-Flanqueadora , Região 5'-Flanqueadora , Alelos , Estudos de Casos e Controles , Estudos de Coortes , DNA Forma Z/química , DNA Forma Z/genética , Éxons , Feminino , Haplótipos , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Desequilíbrio de Ligação , Masculino , Transtornos de Enxaqueca/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/química , Regiões Promotoras Genéticas
5.
Immunol Invest ; 34(2): 143-52, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15921156

RESUMO

OBJECTIVES: To characterize dynamics of changes of serum levels of TGF-beta1 and TNF-alpha in rats with cardiac fibrosis (CF) occurring during chronic renal failure (CRF), and to reveal the character pf correlations of these factors with amounts of cardiac collagen. DESIGN AND METHODS: CRF was induced by unilateral nephrectomy and by electrocoagulation of 25% of the cortex of remnant kidney. Post-operative checkpoints were 2, 4, and 6 months. Serum TGF-beta1 and TNF-alpha levels were measured by ELISA. RESULTS: CF became pronounced only at 6 months of CRF, while serum TGF-beta1 concentrations reached maximum at 4 months, i.e., at the checkpoint preceding the development of CF. Multiple regression showed cardiac collagen to correlate with both serum TGF-beta1 levels and time from the onset of CRF. Sensitivity and specificity of TGF-beta1 as serum marker of CF were 86% and 75%.


Assuntos
Falência Renal Crônica/sangue , Falência Renal Crônica/patologia , Miocárdio/patologia , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/análise , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Fibrose/sangue , Masculino , Ratos , Sensibilidade e Especificidade , Fatores de Tempo , Fator de Crescimento Transformador beta1
6.
J Clin Neurosci ; 10(5): 638-9, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12948479

RESUMO

Krabbe's disease (galactocerebrosidase deficiency) rarely presents in adults, usually with predominantly upper motor neurone clinical features. We report a case in whom the clinical features were similar to motor neurone disease. Nerve conduction studies and neuroimaging were important in leading to the correct diagnosis. Differences in adult-onset presentations are described.


Assuntos
Leucodistrofia de Células Globoides/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Idade de Início , Idoso , Proteínas do Líquido Cefalorraquidiano/análise , Diagnóstico Diferencial , Fasciculação/etiologia , Apraxia da Marcha/etiologia , Humanos , Leucodistrofia de Células Globoides/diagnóstico , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Neurônios Motores/fisiologia , Condução Nervosa/fisiologia , Caminhada
7.
J Telemed Telecare ; 7 Suppl 2: 68-70, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11747665

RESUMO

There is a surprising lack of published experience on the use of videoconferencing in clinical genetics. Patients were randomly allocated to either a telegenetic (cases) or face-to-face (control) conventional clinic. The telegenetic consultation was done by videoconferencing, using ISDN lines at 384 kbit/s. Evaluation by the doctor and counsellor took place immediately after each appointment. The patient was asked to evaluate the appointment by telephone questionnaire about four weeks after the event. Forty-two patients were invited to participate and 33 (79%) returned their consent forms. Four patients declined to participate and were seen in ordinary face-to-face clinics. Preliminary results showed that the assessment of the telegenetics consultations by doctors, counsellors and patients was very favourable, and they responded positively when asked if they would be happy to use telemedicine in the future. For use in selected consultations, videoconferencing does appear to fulfil a useful role in clinical genetics.


Assuntos
Aconselhamento Genético/métodos , Consulta Remota/normas , Atitude do Pessoal de Saúde , Terminais de Computador , Aconselhamento Genético/normas , Humanos , Satisfação do Paciente , Queensland
8.
Ann Surg Oncol ; 8(9): 729-40, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11597015

RESUMO

BACKGROUND: Disruption of normal mechanisms for cell cycle regulation is important in carcinogenesis. SAK and PLK are members of the polo family of serine threonine kinases, which in lower organisms have been shown to be required for the precise regulation of mitosis. Studies of human polo family members have focused on PLK, which has been found to be overexpressed in several tumor types, with the degree of overexpression correlating with adverse clinical outcome. However, PLK expression had not previously been analyzed in colorectal cancer. SAK, a polo family member with unique properties, had not been systematically studied in any tumor type. METHODS: In this study, SAK expression was evaluated in a series of sporadic human colorectal cancer specimens (n = 74) and compared with that of PLK. Expression was assessed by reverse transcription-polymerase chain reaction. RESULTS: In the majority of cases, both SAK and PLK were more highly expressed in tumor tissue than in adjacent normal intestinal mucosa. Levels of SAK and PLK expression in tumor relative to paired normal mucosa correlated directly with patient age and with each other but did not correlate with tumor stage. These results suggest a mechanism for augmented disruption of mitotic regulation in older patients. CONCLUSIONS: The polo family mitotic regulators SAK and PLK are both aberrantly expressed in colorectal cancer. The potential prognostic significance of SAK and PLK expression in colorectal cancer will be evaluated in the future.


Assuntos
Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ciclo Celular , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitose , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Quinase 1 Polo-Like
9.
Curr Biol ; 11(6): 441-6, 2001 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-11301255

RESUMO

Polo-like kinases in yeast, flies, and mammals regulate key events in mitosis. Such events include spindle formation at G2/M, the anaphase-promoting complex (APC) at the exit from mitosis, the cleavage structure at cytokinesis, and DNA damage checkpoints in G2/M. Polo-like kinases are distinguished by two C-terminal polo box (pb) motifs, which localize the enzymes to mitotic structures. We previously identified Sak, a novel polo-like kinase found in Drosophila and mammals. Here, we demonstrate that the Sak kinase has a functional pb domain that localizes the enzyme to the nucleolus during G2, to the centrosomes in G2/M, and to the cleavage furrow during cytokinesis. To study the role of Sak in embryo development, we generated a Sak null allele, the first polo-like kinase to be mutated in mice. Sak(-/-) embryos arrested after gastrulation at E7.5, with a marked increase in mitotic and apoptotic cells. Sak(-/-) embryos displayed cells in late anaphase or telophase that continued to express cyclin B1 and phosphorylated histone H3. Our results suggest that Sak is required for the APC-dependent destruction of cyclin B1 and for exit from mitosis in the postgastrulation embryo.


Assuntos
Proteínas de Drosophila , Mitose/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Complexos Ubiquitina-Proteína Ligase , Células 3T3 , Sequência de Aminoácidos , Ciclossomo-Complexo Promotor de Anáfase , Animais , Ciclina B/metabolismo , Ciclina B1 , Histonas/metabolismo , Humanos , Ligases , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitina-Proteína Ligases
10.
Hum Mutat ; 16(5): 408-16, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11058898

RESUMO

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal development of the liver, heart, skeleton, eye, and face. Mutations in the Jagged1 gene (JAG1) have been found to result in the AGS phenotype and both protein truncating mutations and missense mutations have been identified. Using single stranded conformational polymorphism analysis we have screened 22 AGS affected individuals from 19 families for mutations within Jagged1. Twelve distinct Jagged1 mutations were identified in 15 (68.2%) of the 22 AGS cases, seven of which are novel. The mutations include three small deletions (25%), two small insertions (16.6%), three missense mutations (25%), two nonsense mutations (16.6%), and two splice-site mutations (16.6%). These mutations are spread across the entire coding sequence of the gene and most are localized to highly conserved motifs of the protein predicted to be important for Jagged1 function. One-half of the mutations found in this study are located between exons 9 and 12, a region constituting only 12% of the coding sequence. A splice-donor site mutation in intron 11 was shown to cause aberrant splicing of Jagged1 mRNA, consequently terminating translation prematurely in exon 12. The results of this study are consistent with the proposal that either haploinsufficiency for wild type Jagged1 and/or dominant negative effects produced by mutated Jagged1 are responsible for the AGS phenotype.


Assuntos
Síndrome de Alagille/epidemiologia , Síndrome de Alagille/genética , Mutação/genética , Proteínas/genética , Processamento Alternativo/genética , Substituição de Aminoácidos/genética , Austrália/epidemiologia , Proteínas de Ligação ao Cálcio , Linhagem Celular Transformada , Análise Mutacional de DNA , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteína Jagged-1 , Masculino , Proteínas de Membrana , Mutação de Sentido Incorreto/genética , Linhagem , Vigilância da População , Sítios de Splice de RNA/genética , Deleção de Sequência/genética , Proteínas Serrate-Jagged
11.
Am J Med Genet ; 87(2): 168-74, 1999 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-10533031

RESUMO

Friedreich ataxia is an autosomal recessive disorder caused by mutations in the FRDA gene that encodes a 210-amino acid protein called frataxin. An expansion of a GAA trinucleotide repeat in intron 1 of the gene is present in more than 95% of mutant alleles. Of the 83 people we studied who have mutations in FRDA, 78 are homozygous for an expanded GAA repeat; the other five patients have an expansion in one allele and a point mutation in the other. Here we present a detailed clinical and genetic study of a subset of 51 patients homozygous for an expansion of the GAA repeat. We found a correlation between the size of the smaller of the two expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. There was no significant correlation between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size correlated with bladder symptoms and the presence of foot deformity. The duration of disease is correlated with wheelchair use and the presence of diabetes, scoliosis, bladder symptoms and impaired proprioception, and vibration sense but no other complications studied.


Assuntos
Ataxia de Friedreich/genética , Proteínas de Ligação ao Ferro , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Expansão das Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idade de Início , Austrália , Cardiomiopatias/genética , Criança , Pré-Escolar , Consanguinidade , Diabetes Mellitus/genética , Europa (Continente)/etnologia , Feminino , Ataxia de Friedreich/patologia , Ataxia de Friedreich/fisiopatologia , Homozigoto , Humanos , Lactente , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/genética , Propriocepção/genética , Expansão das Repetições de Trinucleotídeos/fisiologia , Doenças da Bexiga Urinária/genética , Cadeiras de Rodas , Frataxina
13.
J Med Genet ; 36(3): 258-9, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10204858

RESUMO

Segregation ratio distortion (SRD) with preferential transmission of expanded CAG alleles has been reported in Machado-Joseph disease (MJD/SCA3), spinocerebellar ataxia type I (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the transmission frequencies of alleles in normal heterozygotes at these disease loci in 377 pairs of twins and their parents and find no evidence for SRD.


Assuntos
Alelos , Segregação de Cromossomos , Doença de Machado-Joseph/genética , Doenças Neurodegenerativas/genética , Degenerações Espinocerebelares/genética , Repetições de Trinucleotídeos , Gêmeos , Adolescente , Adulto , Humanos
14.
Nat Genet ; 20(1): 25-30, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9731525

RESUMO

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.


Assuntos
Encéfalo/metabolismo , Deficiência Intelectual/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Cromossomo X , Animais , Sequência de Bases , Células COS , Clonagem Molecular , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA , Quinases Ativadas por p21
15.
Exp Neurol ; 150(2): 213-22, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9527890

RESUMO

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with a CAG trinucleotide repeat expansion in a large gene on chromosome 4. The gene encodes the protein huntingtin with a polyglutamine tract encoded by the CAG repeat at the N-terminus. The number of CAG repeats in HD are significantly increased (36 to 120+) compared with the normal population (8-39). The pathological mechanism associated with the expanded CAG repeat in HD is not clear but there is evidence that polyglutamine is directly neurotoxic. We have immunolocalized huntingtin with an in-house, well-characterised, polyclonal antibody in HD, Alzheimer's disease (AD), and Picks disease (PiD) brains. Control brain tissue sections were from head injured and cerebral ischaemia cases. In HD, huntingtin was immunopositive in the surviving but damaged neurons and reactive astrocytes of the caudate and putamen. However, in AD and PiD the immunostaining was largely restricted to the characteristic intracellular inclusion bodies associated with the disease process in each case. In AD, huntingtin was localized only in the intracellular neurofibrillary tangles and dystrophic neurites within the neuritic amyloid plaques but not with the amyloid. In PiD, strongly positive huntingtin immunostaining was present within cytoplasmic Pick bodies. Our findings suggest huntingtin selectively accumulates in association with abnormal intracytoplasmic and cytoskeletal filaments of neurons and glia in neurodegenerative diseases such as HD, AD, and PiD. Cells in the CNS appear sensitive to damage by the aggregated, toxic levels of huntingtin and evidence of its interaction with neurofilaments could provide information about its potential role in the aetiology of HD.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Demência/patologia , Doença de Huntington/patologia , Proteínas do Tecido Nervoso/análise , Emaranhados Neurofibrilares/patologia , Proteínas Nucleares/análise , Adulto , Idoso , Peptídeos beta-Amiloides/análise , Citoesqueleto/patologia , Feminino , Proteína Glial Fibrilar Ácida/análise , Humanos , Proteína Huntingtina , Masculino , Pessoa de Meia-Idade , Neuritos/patologia , Neuroglia/patologia , Neurônios/patologia , Proteínas tau/análise
16.
Baillieres Clin Gastroenterol ; 12(2): 275-91, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9890073

RESUMO

Alagille syndrome (AS) (arteriohepatic dysplasia, Alagille-Watson syndrome) is a multi-system disorder with hepatic, skeletal, eye, cardiac and renal manifestations. It results from mutation of the JAG1 gene, located on chromosome 20, which encodes a ligand for Notch receptor(s). The interactions of Notch receptors and their ligands are crucial in controlling cell fate decisions in a variety of developmental processes. AS varies in its severity, even in the same family, from asymptomatic gene carriers through to lethality due to inoperable cardiac or end-stage liver disease. However, advances in medical and surgical therapy have improved the prognosis at the severe end of the spectrum. It is hoped that the enhanced understanding of the biology of AS resulting from the cloning of the JAG1 gene will enable us to develop additional strategies for more effective treatments.


Assuntos
Síndrome de Alagille , Síndrome de Alagille/genética , Síndrome de Alagille/terapia , Humanos
17.
Mov Disord ; 12(4): 519-30, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9251070

RESUMO

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that clinically overlaps with Huntington's disease (HD) and manifests combinations of chorea, myoclonus, seizures, ataxia, and dementia. DRPLA is caused by a CAG triplet repeat (CTG-B37) expansion coding for polyglutamine on chromosome 12 and exhibits the genetic phenomenon of anticipation. This neurodegenerative disease has only rarely been reported in non-Japanese pedigrees, and there are only a few neuropathological studies in genetically confirmed patients. We report 10 cases of DRPLA from two North American and two British pedigrees in which CTG-B37 expansions have been demonstrated within each kindred (54-83 repeats), individually in 8 of the 10 cases, and describe the neuropathological findings in 4 cases. Members of DRPLA kindreds have a wide range of clinical phenotypes and markedly variable ages at onset. The neuropathological spectrum is centered around the cerebellifugal and pallidofugal systems, but neurodegenerative changes can be found in many nuclei, tracts, and systems. Evidence of CTG-B37 triplet repeat expansion should be sought in HD-like cases that are negative for expanded triplet repeats within the HD IT15 gene or in autopsy cases with degeneration of the dentatorubral or pallidoluysian systems.


Assuntos
Encefalopatias/genética , Encéfalo/patologia , Transtornos dos Movimentos/genética , Adulto , Atrofia , População Negra/genética , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico , Encefalopatias/etnologia , Encefalopatias/fisiopatologia , Criança , Cromossomos Humanos Par 12/genética , Giro Denteado/patologia , Diagnóstico Diferencial , Feminino , Globo Pálido/patologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etnologia , Transtornos dos Movimentos/fisiopatologia , Degeneração Neural/genética , Linhagem , Fenótipo , Núcleo Rubro/patologia , Repetições de Trinucleotídeos , Reino Unido , Estados Unidos , População Branca/genética
18.
Hum Mol Genet ; 5(4): 481-7, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8845840

RESUMO

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of a CAG repeat in a gene coding for a protein of unknown function. We have raised a polyclonal antibody against a 12 amino acid peptide (residues 2110-2121 of human huntingtin) which specifically recognises huntingtin on Western blots of human, rat and mouse brain. We have characterised huntingtin expression in the mouse. The protein was detected on Western blots of all mouse tissues examined, with the highest expression seen in brain. Human, mouse and rat brain were fractionated by differential centrifugation and discontinuous Percoll gradients. The fractions were analysed by Western blotting for huntingtin and synaptophysin (a synaptic vesicle localised protein). In mouse brain, huntingtin was localised in the soluble S3 fraction; in rat brain it was localised in the soluble S3 fraction and also in the membrane P2 and P3 fractions; in both normal and HD-affected human brain, huntingtin was membrane bound with a distribution essentially the same as that of synaptophysin. These observed differences in the subcellular localisation of huntingtin between mouse and human brain are important in the context of mouse models for HD.


Assuntos
Encéfalo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Adulto , Sequência de Aminoácidos , Animais , Anticorpos/imunologia , Western Blotting , Humanos , Proteína Huntingtina , Masculino , Camundongos , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Ratos , Frações Subcelulares
19.
J Neurol Neurosurg Psychiatry ; 60(1): 78-81, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8558157

RESUMO

OBJECTIVE: To correlate the degree of CAG repeat expansion with neuropathological findings in Huntington's disease. METHODS: The CAG repeat polymorphism was analysed in a large series of brain samples from 268 patients with a clinical diagnosis of Huntington's disease in which full neuropathological data was available. RESULTS: Analysis by polymerase chain reaction was successful in 63% of samples (169 of 268). Repeat expansions were detected in 152 of 153 (99%) samples with a neuropathological diagnosis of Huntington's disease. The exceptional case (22 CAG repeats) showed mild but definite pathological changes and had a typical clinical illness with a positive family history; it raises the possibility that an alternative mutation in the Huntington's disease gene may be responsible although it is more likely that a mutation in another gene has resulted in an Huntington's disease-like phenotype. Four of 16 cases without pathological changes of Huntington's disease also possessed an expanded repeat sequence; a glioblastoma masked the pathological changes of Huntington's disease in one case but the other three cases had a typical clinical history and a positive family history. These three cases may reliably be classified as Vonsattel's Huntington's disease grade 0. Three of 12 cases with a normal repeat length and no morphological changes of Huntington's disease showed other neuropathology; two had Alzheimer's disease and the other had multiple sclerosis. Review of the clinical notes of two other cases indicated a diagnosis of tardive dyskinesia complicating phenothiazine treatment of schizophrenia. The remaining pathology negative/expansion negative cases had been referred because of a family history of Huntington's disease; all but one were themselves symptom free. Apart from emphasising the possibility that an alternative mutation may result in a clinical phenocopy of Huntington's disease, this case suggests that such a clinical phenocopy may occur without gross or light microscopical neuropathological changes (Vonsattel's Huntington's disease grade 0). CONCLUSIONS: The study confirms the value of molecular genetic analysis in cases of suspected Huntington's disease and shows the importance of detailed neuropathological study in the few cases of suspected Huntington's disease with normal CAG repeat lengths.


Assuntos
DNA , Doença de Huntington/genética , Doença de Huntington/patologia , Polimorfismo Genético , Repetições de Trinucleotídeos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Doença de Huntington/classificação , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Método Simples-Cego
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