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1.
Mol Psychiatry ; 22(6): 836-849, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27240531

RESUMO

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.


Assuntos
Transtorno Autístico/genética , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 16/fisiologia , Obesidade/genética , Adolescente , Adulto , Idoso , Transtorno do Espectro Autista/genética , Índice de Massa Corporal , Criança , Pré-Escolar , Cromatina/metabolismo , Cromatina/fisiologia , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Masculino , Megalencefalia/genética , Microcefalia/genética , Pessoa de Meia-Idade , Fenótipo
2.
Mol Psychiatry ; 19(3): 368-79, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23587880

RESUMO

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.


Assuntos
Ansiedade/genética , Transtorno Bipolar/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Mutação
3.
Neurology ; 78(16): 1250-7, 2012 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-22491860

RESUMO

OBJECTIVES: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families. METHODS: Families with EOFAD genetically linked to the APP region were screened for missense mutations and locus duplications of APP. Further, using genome-wide DNA microarray data, we examined the APP locus for CNVs in a total of 797 additional early- and late-onset AD pedigrees. Finally, 423 single nucleotide polymorphisms (SNPs) in the APP locus, including 2 promoter polymorphisms previously associated with AD risk, were tested in up to 4,200 individuals from multiplex AD families. RESULTS: Analyses of 8 21q21-linked families revealed one family carrying a nonsynonymous mutation in exon 17 (Val717Leu) and another family with a partially penetrant 3.5-Mb locus duplication encompassing APP. CNV analysis in the APP locus revealed an additional family carrying a fully penetrant 380-kb duplication, merely spanning APP. Last, contrary to previous reports, association analyses of more than 400 different SNPs in or near APP failed to show significant effects on AD risk. CONCLUSION: Our study shows that APP mutations and locus duplications are a very rare cause of EOFAD and that the contribution of common APP variants to AD susceptibility is insignificant. Furthermore, duplications of APP may not be fully penetrant, possibly indicating the existence of hitherto unknown protective genetic factors.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Predisposição Genética para Doença/genética , Idoso , Variações do Número de Cópias de DNA , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Linhagem , Polimorfismo de Nucleotídeo Único
4.
Neurology ; 78(10): 690-5, 2012 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-22323755

RESUMO

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.


Assuntos
Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Idade de Início , Alelos , Feminino , Genótipo , Humanos , Doença de Huntington/diagnóstico , Masculino
5.
Am J Med Genet B Neuropsychiatr Genet ; 150B(6): 762-81, 2009 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-19388013

RESUMO

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision-making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress-based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for approximately 30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Tomada de Decisões , Emoções/fisiologia , Expressão Facial , Recompensa , Adulto , Tonsila do Cerebelo/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Lobo Frontal/fisiologia , Genótipo , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Polimorfismo Genético
6.
J Med Genet ; 46(4): 242-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18805830

RESUMO

BACKGROUND: Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. PATIENTS: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. RESULTS: We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. CONCLUSIONS: The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.


Assuntos
Transtorno Autístico/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 15/genética , Deficiência Intelectual/genética , Adolescente , Transtorno Autístico/patologia , Criança , Pré-Escolar , Deleção Cromossômica , Hibridização Genômica Comparativa , Feminino , Duplicação Gênica , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Fenótipo , Adulto Jovem
7.
Neurology ; 71(1): 28-34, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18509094

RESUMO

BACKGROUND: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. METHODS: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. RESULTS: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. CONCLUSIONS: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.


Assuntos
Expressão Gênica/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Doença de Parkinson/genética , Proteínas tau/genética , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Análise Mutacional de DNA , Expansão das Repetições de DNA/genética , Feminino , Testes Genéticos , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genética
8.
J Med Genet ; 44(11): 695-701, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17660463

RESUMO

BACKGROUND: The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene. RESULTS: In this study, we used a collection of 112 sperm DNAs from male HD gene-positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat-length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father-offspring and 311 mother-offspring pairs in this Venezuelan pedigree. Repeat-length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat-length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring. CONCLUSION: Significant sibling-sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.


Assuntos
Doença de Huntington/genética , Instabilidade de Microssatélites , Repetições Minissatélites/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Ordem de Nascimento , Criança , Pai , Feminino , Heterozigoto , Humanos , Proteína Huntingtina , Doença de Huntington/epidemiologia , Masculino , Mães , Pais , Linhagem , Fatores Sexuais , Irmãos , Espermatozoides/química , Venezuela/epidemiologia
9.
Neurology ; 67(12): 2206-10, 2006 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-17190945

RESUMO

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.


Assuntos
Glutationa S-Transferase pi/genética , Herbicidas/efeitos adversos , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Doença de Parkinson Secundária/genética , Medição de Risco/métodos , Suscetibilidade a Doenças/induzido quimicamente , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/induzido quimicamente , Fatores de Risco
10.
Med Educ ; 40(1): 26-35, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16441320

RESUMO

OBJECTIVE: To follow the progress of young female adolescents, as risk-taking standardised patients (SPs), and to monitor for adverse affects that role-playing may have on the adolescents. METHODS: A prospective design was used in which 11 female adolescents, aged 13-15 years, were recruited from 2 schools. The adolescents were trained to portray risk-taking individuals with a medical condition and were interviewed with their SP mother by final-year medical students 1-3 times a month over 6-14 months. A control group was selected from both schools (n = 6). Main outcome measures were pre- and post-interviews using standardised questionnaires [Achenbach's Youth Self-Report (YSR) and Piers Harris Children's Self Concept Scale (SCS),] and focus groups. RESULTS: The adolescent group simulated 111 interviews (mean per adolescent 10.1, SD = 6.2) each lasting 60-70 minutes. QUANTITATIVE DATA: The pre- and post-scores from the YSR and SCS demonstrated no significant differences within the SP study participants or between the control group vs. the study group. FOCUS GROUP FINDINGS: The initial focus group acted as a debriefing exercise and prompted the adolescents to request that they come out of their role when giving feedback. Subsequent focus group discussion was around the medical student performance and their family doctors. CONCLUSION: Adolescent females showed no adverse effects when used extensively to portray risk-taking SPs. The focus groups provided the adolescents with an opportunity to debrief together. The adolescent SPs reported benefiting from this study but requested unanimously that they come "out of character" when giving feedback to the medical students.


Assuntos
Transtornos de Ansiedade/etiologia , Educação de Graduação em Medicina/métodos , Transtornos do Humor/etiologia , Simulação de Paciente , Ensino/métodos , Adolescente , Atitude Frente a Saúde , Feminino , Humanos , Nova Escócia , Estudos Prospectivos , Assunção de Riscos , Desempenho de Papéis
11.
Neurology ; 65(11): 1823-5, 2005 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-16344533

RESUMO

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Transtornos Parkinsonianos/genética , Polimorfismo Genético/genética , Idade de Início , Análise Mutacional de DNA , Saúde da Família , Frequência do Gene , Testes Genéticos , Haplótipos/genética , Homozigoto , Modelos Estatísticos , Transtornos Parkinsonianos/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
13.
Mov Disord ; 20(9): 1188-91, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15966003

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Fatores de Transcrição/genética , alfa-Sinucleína/genética , Idoso , Deleção de Genes , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Pessoa de Meia-Idade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Mutação Puntual/genética , Reação em Cadeia da Polimerase , Proteína Desglicase DJ-1 , Fatores de Risco
14.
Neurology ; 61(11): 1557-61, 2003 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-14663042

RESUMO

OBJECTIVE: To identify a haplotype influencing onset age for Parkinson's disease (PD) in the PARK3 region on chromosome 2p13. METHODS: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. RESULTS: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP-rs2421095, rs1876487, rs1561244-revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005). CONCLUSIONS: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.


Assuntos
Cromossomos Humanos Par 2 , Doença de Parkinson/genética , Adolescente , Adulto , Idade de Início , Idoso , Oxirredutases do Álcool/genética , Mapeamento Cromossômico , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Polimorfismo de Nucleotídeo Único
15.
Am J Med Genet A ; 119A(3): 279-82, 2003 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12784292

RESUMO

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.


Assuntos
Doença de Huntington/genética , Repetições de Trinucleotídeos , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , New England , Probabilidade , Taxa de Sobrevida
16.
Can Child Adolesc Psychiatr Rev ; 12(4): 110-2, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19030153

RESUMO

Thirty-five adolescent girls with eating disorders completed a new brief measure of motivational stage of change and decisional balance. The study supported Prochaska's model of behavioral change demonstrating that decision making was consistently related to stage of readiness to change. The girls generated their individual pros and cons of changing and rated the overall strength of pros and cons. Results showed that the strength of the pros of changing was lowest in Precontemplation and highest in Maintenance. The pros of changing primarily reflected their expectation that "taking action" against the eating disorder would improve their body function and decrease their social anxiety. The cons of changing listed reflected concern that changing would negatively affect their body appearance, and that they were fearful of changing.

17.
DNA Cell Biol ; 20(9): 579-86, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11747609

RESUMO

Our laboratory recently reported that mutations in the human I-kappaB kinase-associated protein (IKBKAP) gene are responsible for familial dysautonomia (FD). Interestingly, amino acid substitutions in the IKAP correlate with increased risk for childhood bronchial asthma. Here, we report the cloning and genomic characterization of the mouse Ikbkap gene, the homolog of human IKBKAP. Like its human counterpart, Ikbkap encodes a protein of 1332 amino acids with a molecular weight of approximately 150 kDa. The Ikbkap gene product, Ikap, contains 37 exons that span approximately 51 kb. The protein shows 80% amino acid identity with human IKAP. It shows very high conservation across species and is homologous to the yeast Elp1/Iki3p protein, which is a member of the Elongator complex. The Ikbkap gene maps to chromosome 4 in a region that is syntenic to human chromosome 9q31.3. Because no animal model of FD currently exists, cloning of the mouse Ikbkap gene is an important first step toward creating a mouse model for FD. In addition, cloning of Ikbkap is crucial to the characterization of the putative mammalian Elongator complex.


Assuntos
Proteínas de Transporte/genética , Sequência de Aminoácidos , Animais , Clonagem Molecular , DNA Complementar/análise , DNA Complementar/genética , Disautonomia Familiar/genética , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Dados de Sequência Molecular , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
18.
Neurology ; 57(6): 1124-6, 2001 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-11571351

RESUMO

A genome-wide scan for idiopathic PD in a sample of 113 PD-affected sibling pairs is reported. Suggestive evidence for linkage was found for chromosomes 1 (214 cM, lod = 1.20), 9 (136 cM, lod = 1.30), 10 (88 cM, lod = 1.07), and 16 (114 cM, lod = 0.93). The chromosome 9 region overlaps the genes for dopamine beta-hydroxylase and torsion dystonia. Although no strong evidence for linkage was found for any locus, these results may be of value in comparison with similar studies by others.


Assuntos
Testes Genéticos , Genoma , Doença de Parkinson/genética , Idoso , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 9 , Dopamina beta-Hidroxilase/genética , Distonia Muscular Deformante/genética , Ligação Genética/genética , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico
19.
Am J Hum Genet ; 68(3): 598-605, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11179008

RESUMO

Familial dysautonomia (FD; also known as "Riley-Day syndrome"), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we had mapped the FD gene, DYS, to a 0.5-cM region on chromosome 9q31 and had shown that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its five genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wild-type message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wild-type, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in four patients is a missense (R696P) mutation in exon 19, which is predicted to disrupt a potential phosphorylation site. Our findings indicate that almost all cases of FD are caused by an unusual splice defect that displays tissue-specific expression; and they also provide the basis for rapid carrier screening in the Ashkenazi Jewish population.


Assuntos
Processamento Alternativo , Cromossomos Humanos Par 9 , Disautonomia Familiar/genética , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Substituição de Aminoácidos , Encéfalo/metabolismo , Mapeamento Cromossômico , Clonagem Molecular , Éxons , Marcadores Genéticos , Humanos , Quinase I-kappa B , Linfócitos/fisiologia , Dados de Sequência Molecular , RNA/sangue , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica
20.
Ann Neurol ; 49(1): 29-34, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11198293

RESUMO

Morphometric studies of the tail of the caudate nucleus, the site where the pathology is first seen, were performed on 16 brain specimens collected from individuals at risk for inheriting Huntington's disease (HD). Medical records and information obtained from immediate family members indicated that all had died without symptoms of HD. Six individuals had 37 or more CAG repeats and were designated HD gene carriers, whereas 10 were determined to be non-carriers. Cell counts of the tail of the caudate nucleus revealed an increased density of oligodendrocytes among the presymptomatic HD gene carriers (mean cells/field: carriers = 40.0, noncarrier = 21.3; age, sex, repeated measure adjusted F[126] = 11.7, p = 0.0008). No statistically significant differences were found between HD carriers and noncarriers in the density of neurons (carriers = 16.9, noncarriers = 15.5), astrocytes (carriers = 27.8, noncarriers = 21.3) or microglial cells (carriers = 7.9, noncarriers = 5.6). Ubiquitin immunostaining performed in 3 gene carriers revealed intranuclear inclusions in all 3 cases, including 1, with 37 repeats, who died 3 decades before the expected age for onset of the clinical syndrome. Normal densities of other cell types and careful macroscopic examination suggest that the increase in oligodendroglial density is not a consequence of atrophy and may instead reflect a developmental effect of the HD gene.


Assuntos
Núcleo Caudado/patologia , Doença de Huntington/patologia , Adulto , Idoso , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade
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