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1.
Clin Genet ; 93(3): 632-639, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28857138

RESUMO

Ellis-van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.


Assuntos
Alelos , Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/diagnóstico , Síndrome de Ellis-Van Creveld/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Razão de Chances , Linhagem , Fenótipo , Radiografia , Sequenciamento do Exoma , Adulto Jovem
2.
Acta Psychiatr Scand ; 135(6): 527-538, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28256707

RESUMO

OBJECTIVE: To systematically examine the effects of dopaminergic agents (modafinil, armodafinil, pramipexole, methylphenidate, and amphetamines) on bipolar depression outcomes. METHODS: Meta-analysis of randomized controlled trials was performed to assess the efficacy and safety of treatment with dopaminergic agents in bipolar depression. In a secondary analysis, findings from both randomized controlled trials and high-quality observational studies were pooled by means of meta-analytic procedures to explore dopaminergic treatment-related new mania. RESULTS: Nine studies (1716 patients) were included in our meta-analysis of randomized controlled trials. Treatment with dopaminergic agents for bipolar depression was associated with an increase in both response (1671 individuals, RR 1.25, 95% CI 1.05 to 1.50) and remission rates (1671 individuals, RR 1.40, 95% CI 1.14, 1.71). There was no evidence of an increased risk of mood switch associated with this treatment (1646 individuals, RR 0.96, 95% CI 0.49, 1.89). Our secondary analysis (1231 individuals) yielded a cumulative incidence of mood switch of 3% (95% CI 1.0, 5.0) during a mean follow-up period of 7.5 months. CONCLUSIONS: Preliminary findings suggest that dopaminergic agents may represent a useful alternative for the treatment of bipolar depression, with no evidence for a related increase in the risk of mood destabilization during short-term follow-up.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Dopaminérgicos/uso terapêutico , Humanos , Resultado do Tratamento
3.
J Breath Res ; 10(4): 046013, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27869103

RESUMO

The two phenotypes of both limited and diffuse systemic sclerosis (SSc) have different forms of pulmonary involvement: pulmonary arterial hypertension (limited phenotype) or interstitial lung disease (ILD) (diffuse phenotype). We aimed to investigate whether Th17-related cytokines, as measured in exhaled breath condensate (EBC) and in serum were connected to ILD in diffuse SSc patients. We found that for both limited and diffuse SSc, the EBC levels of all cytokines and most of the cytokine serum levels were significantly higher in patients than in controls, while, the EBC levels of Th-17 cytokines and the serum levels of IL-10 and TNF-α were significantly higher in diffuse than in limited SSc. Moreover, the thoracic CT-scan score of ILD was significantly associated with the EBC levels of IL-1 beta and with the serum IL-23, TNF-α and IL-10 levels, whereas lung carbon monoxide diffusing capacity was negatively related to the EBC levels of IL-1 beta, IL-17 and serum IL-10. Serum IL-23 was also inversely correlated with vital capacity. In conclusion, in diffuse SSc patients our results show a clear link between Th-17 cytokines measured both in EBC and in serum with interstitial lung involvement. This highlights how important it is to target Th-17 cytokines when developing new treatments for lung fibrosis.


Assuntos
Testes Respiratórios/métodos , Citocinas/metabolismo , Interleucina-17/metabolismo , Doenças Pulmonares Intersticiais/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Neuroscience ; 286: 162-70, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25481234

RESUMO

Steroid hormones are important players to regulate adult neurogenesis in the dentate gyrus of the hippocampus, but their involvement in the regulation of the same phenomenon in the subventricular zone (SVZ) of the lateral ventricles is not completely understood. Here, in male rats, we tested the existence of activational effects of testosterone (T) on cell proliferation in the adult SVZ. To this aim, three groups of male rats: castrated, castrated and treated with T, and controls were treated with 5-bromo-2'-deoxyuridine (BrdU) and killed after 24h. The density of BrdU-labeled cells was significantly lower in castrated animals in comparison to the other two groups, thus supporting a direct correlation between SVZ proliferation and levels of circulating T. To clarify whether this effect is purely androgen-dependent, or mediated by the T metabolites, estradiol (E2) and dihydrotestosterone (DHT), we evaluated SVZ proliferation in castrated males treated with E2, DHT and E2+DHT, in comparison to T- and vehicle-treated animals, and sham-operated controls. The stereological analysis demonstrated that E2 and T, but not DHT, increase proliferation in the SVZ of adult male rats. Quantitative evaluation of cells expressing the endogenous marker of cell proliferation phosphorylated form of Histone H3 (PHH3), or the marker of highly dividing SVZ progenitors Mash1, indicated the effect of T/E2 is mostly restricted to SVZ proliferating progenitors. The same experimental protocol was repeated on ovariectomized female rats treated with E2 or T. In this case, no statistically significant difference was found among groups. Overall, our results clearly show that the gonadal hormones T and E2 represent important mediators of cell proliferation in the adult SVZ. Moreover, we show that such an effect is restricted to males, supporting adult neurogenesis in rats is a process differentially modulated in the two sexes.


Assuntos
Proliferação de Células , Estradiol/fisiologia , Ventrículos Laterais/fisiologia , Neurogênese , Testosterona/fisiologia , Animais , Bromodesoxiuridina/análise , Castração , Estradiol/farmacologia , Feminino , Ventrículos Laterais/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Testosterona/metabolismo , Testosterona/farmacologia
5.
J Med Genet ; 45(1): 36-42, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17693570

RESUMO

BACKGROUND: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. METHODS: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. RESULTS: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. CONCLUSION: DLG5 30Q is associated with a small reduction in risk of CD in women.


Assuntos
Alelos , Doença de Crohn/genética , Frequência do Gene , População Branca/genética , Estudos de Casos e Controles , Doença de Crohn/etnologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Razão de Chances , Fatores Sexuais , Proteínas Supressoras de Tumor/genética
6.
Bone Marrow Transplant ; 40(3): 283-5, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17529999
8.
Artigo em Inglês | MEDLINE | ID: mdl-15703003

RESUMO

This study describes the effect of parity (multiparous versus primiparous) and body condition score (BCS) at calving (<3 or > or =3; scale 1-5) on variations of BCS, body weight (BW) and metabolic profiles in Holstein cows grazing on improved pastures. Forty-two cows were studied (21 multiparous and 21 primiparous) from 2 months before to 3 months after calving. BCS, BW and milk production were measured every 2 weeks. Blood samples were taken every 2 weeks to determine total protein, albumin, urea, non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), cholesterol, aspartate aminotransferase (AST), calcium, phosphorus and magnesium. Primiparous cows had lower BCS during the early postpartum (PP) period and produced less milk than multiparous. In primiparous cows NEFA concentrations were higher during the early postpartum period; BHB levels were similar in both categories during this period. Primiparous cows showed a more unbalanced metabolic profile than multiparous cows, reflecting that they are recovering from the loss of BCS after calving with less success.


Assuntos
Ração Animal , Bovinos/fisiologia , Leite/metabolismo , Paridade , Poaceae , Animais , Composição Corporal/fisiologia , Constituição Corporal/fisiologia , Bovinos/sangue , Bovinos/metabolismo , Feminino , Lactação/sangue , Lactação/metabolismo , Lactação/fisiologia , Período Pós-Parto/sangue , Gravidez
10.
Phys Rev Lett ; 89(1): 011301, 2002 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12097025

RESUMO

Observations of neutral-current nu interactions on deuterium in the Sudbury Neutrino Observatory are reported. Using the neutral current (NC), elastic scattering, and charged current reactions and assuming the standard 8B shape, the nu(e) component of the 8B solar flux is phis(e) = 1.76(+0.05)(-0.05)(stat)(+0.09)(-0.09)(syst) x 10(6) cm(-2) s(-1) for a kinetic energy threshold of 5 MeV. The non-nu(e) component is phi(mu)(tau) = 3.41(+0.45)(-0.45)(stat)(+0.48)(-0.45)(syst) x 10(6) cm(-2) s(-1), 5.3sigma greater than zero, providing strong evidence for solar nu(e) flavor transformation. The total flux measured with the NC reaction is phi(NC) = 5.09(+0.44)(-0.43)(stat)(+0.46)(-0.43)(syst) x 10(6) cm(-2) s(-1), consistent with solar models.

11.
Phys Rev Lett ; 89(1): 011302, 2002 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12097026

RESUMO

The Sudbury Neutrino Observatory (SNO) has measured day and night solar neutrino energy spectra and rates. For charged current events, assuming an undistorted 8B spectrum, the night minus day rate is 14.0%+/-6.3%(+1.5%)(-1.4%) of the average rate. If the total flux of active neutrinos is additionally constrained to have no asymmetry, the nu(e) asymmetry is found to be 7.0%+/-4.9%(+1.3%)(-1.2%). A global solar neutrino analysis in terms of matter-enhanced oscillations of two active flavors strongly favors the large mixing angle solution.

12.
Clin Genet ; 61(6): 459-64, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12121355

RESUMO

Mutations in the Connexin 26 (Cx26) gene have been found to account for approximately 20% of all childhood deafness. This number approaches 50% in documented recessive cases of hearing loss. Two mutations, 35delG and 167delT, account for the majority of reported mutations in this gene, but to date, more than 60 mutations have been described. No other single gene has yet been identified that contributes this significantly to the aetiology of hearing loss. Several mutations in this gene have been found to predominate in specific ethnic populations (167delT in Ashkenazi Jews and 235delC in Japanese individuals). While the majority of mutations found in Cx26 result in frame shifts and premature terminations, a number of missense mutations have also been identified. The V37I missense mutation has been reported as both a polymorphism and as a potentially disease-causing missense mutation. The present authors have identified three unrelated individuals with sensorineural hearing loss who are homozygous for this mutation. One individual is of Philippine ancestry, another is from a Chinese and Cambodian background, while the third is of Chinese ancestry, raising the possibility that this mutation may be more frequent among populations in eastern Asia.


Assuntos
Conexinas/genética , Perda Auditiva Neurossensorial/genética , Homozigoto , Mutação de Sentido Incorreto , Criança , Pré-Escolar , Conexina 26 , Análise Mutacional de DNA , Feminino , Perda Auditiva Neurossensorial/etnologia , Humanos , Masculino , Mutação Puntual
13.
Cephalalgia ; 22(1): 33-6, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11993611

RESUMO

Nitrite concentrations in plasma were investigated in a population of migraine and cluster headache patients and a group of healthy non-headache controls. A hundred migraine patients and 69 cluster headache patients in the interictal period, and 112 controls, were studied. Significantly higher nitrite concentrations were found in migraine patients, with and without aura, and cluster headache patients, in remission and cluster phase, than in controls. These findings suggest that a basal dysfunction in the L-arginine-NO pathway may be involved in the peripheral mechanisms predisposing subjects with neurovascular headaches to individual attacks.


Assuntos
Arginina/sangue , Cefaleia Histamínica/enzimologia , Transtornos de Enxaqueca/enzimologia , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico/fisiologia , Nitritos/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência
14.
Neurol Sci ; 23 Suppl 2: S117-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12548371

RESUMO

The Parkin gene is responsible for about 50% of autosomal recessive juvenile parkinsonism (ARJP) and less than 20% of sporadic early onset cases. We recently mapped a novel ARJP locus (PARK6) on chromosome 1p. Linkage to PARK6 was confirmed in 8 families from 4 different European countries. These families share some clinical features with the European Parkin-positive cases, with a wide range of ages at onset and slow progression. However, features typical of ARJP, such as dystonia and sleep benefit, were not observed, making the clinical presentation of late-onset cases indistinguishable from that of idiopathic PD. The determination of the smallest region of homozygosity in one consanguineous family allowed reducing the candidate interval to 9 cM. PARK6 appears to be an important locus for ARJP in Europe.


Assuntos
Ligases/genética , Transtornos Parkinsonianos/genética , Ubiquitina-Proteína Ligases , Cromossomos Humanos Par 1 , Europa (Continente)/epidemiologia , Ligação Genética , Genótipo , Humanos , Transtornos Parkinsonianos/epidemiologia , Linhagem
15.
Mov Disord ; 16(6): 999-1006, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11748730

RESUMO

The clinical features of nine patients (three women and six men) affected by PARK6-linked parkinsonism, belonging to three unrelated Italian families, are reported. The occurrence of affected men and women within one generation suggested an autosomal recessive mode of inheritance in all three families. Mean age at disease onset was 36 +/- 4.6 years; all cases except one presented with asymmetrical signs, consisting of tremor and akinesia of one upper limb or unilateral short step gait. Affected individuals had a mean age of 57 +/- 8.5 years, and average disease duration was 21 +/- 7.8 years. Parkinsonian features included benign course, early onset of drug-induced dyskinesias, and a good and persistent response to levodopa. There were no other associated features (i.e., pyramidal or cerebellar signs, dysautonomia, or diurnal fluctuations unrelated to drug treatment). Cognition was unaffected. The clinical picture was remarkably similar in all patients; no relevant family-related differences were found. PARK6 disease is a new form of early-onset parkinsonism without other atypical clinical features.


Assuntos
Cromossomos Humanos Par 1/genética , Genes Recessivos/genética , Transtornos Parkinsonianos/genética , Adulto , Idade de Início , Idoso , Diagnóstico Diferencial , Progressão da Doença , Discinesia Induzida por Medicamentos/genética , Feminino , Lateralidade Funcional , Transtornos Neurológicos da Marcha/genética , Haplótipos , Humanos , Itália/epidemiologia , Levodopa/efeitos adversos , Escore Lod , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/fisiopatologia , Linhagem , Fenótipo , Síndrome , Tremor/genética , Gravação de Videoteipe
16.
Anim Reprod Sci ; 68(1-2): 45-56, 2001 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-11600273

RESUMO

This study characterized endometrial expression of mRNAs of oestrogen and progesterone receptors (ER, PR) and insulin-like growth factor-I (IGF-I) during the oestrous cycle. Seven Holstein heifers that showed standing oestrus on the same day (day 0) were selected and blood samples for oestradiol (E2) and progesterone (P4) determinations by RIA were taken daily until day 23. Endometrial samples were taken by transcervical biopsies on days 0, 5, 12 and 19 for mRNA determination by solution hybridization. The highest endometrial mRNA levels of ERalpha and PR were observed at oestrus and a decline was observed already at day 5, which then decreased progressively at the end of the luteal phase. IGF-I mRNA levels were higher at day 0 and 5 than at day 12. At day 19, mRNA levels of ERalpha, PR and IGF-I were the lowest in heifers that were at the end of their luteal phase (n=4), but were high again in heifers which P4 levels were basal (n=3). The temporal changes in mRNA endometrial expression of ERalpha, PR and IGF-I and their relation to the changes in steroid concentrations during the bovine oestrus cycle are described.


Assuntos
Bovinos/fisiologia , Endométrio/metabolismo , Ciclo Estral/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Animais , Northern Blotting , Estradiol/sangue , Receptor alfa de Estrogênio , Feminino , Regulação da Expressão Gênica/fisiologia , Fator de Crescimento Insulin-Like I/genética , Ovário/metabolismo , Progesterona/sangue , RNA Mensageiro/metabolismo , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Fatores de Tempo
17.
Neurol Sci ; 22(1): 95-6, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11487218

RESUMO

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion. Three PTD loci (DYT1, DYT6 and DYT7) have been identified to date. However, in several PTD families linkage to the known loci has been excluded. We identified an Italian PTD family with 11 definitely affected members. Phenotype was characterised by juvenile or early-adult onset, prominent cranial-cervical and upper limb involvement, mild course and occasional generalisation. A genome-wide search performed in the family identified a novel PTD locus (DYT13) within a 22-cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 (theta = 0) between the disease and marker D1S2667.


Assuntos
Cromossomos Humanos Par 1/genética , Distonia Muscular Deformante/genética , Mutação Puntual/genética , Adolescente , Adulto , Idade de Início , Braço/inervação , Braço/fisiopatologia , Criança , Pré-Escolar , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Itália , Masculino , Pescoço/inervação , Pescoço/fisiopatologia , Fenótipo
18.
Ann Hematol ; 80(6): 340-4, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11475147

RESUMO

The relative incidence of Hodgkin's disease (HD) has been found to have increased approximately seven times in HIV-infected patients. We analyzed the histological distribution of HIV-associated HD with the aim of clarifying purported difference(s) from de novo HD. References on HIV/AIDS-associated HD were retrieved from the most complete databases. Nineteen articles were the subject of our analysis. Seventeen of them reported data on the histological type of HIV/AIDS-associated HD patients; the route of infection and age of the patients were also considered when available. According to the Peto's methodology, histological types were compared with those from two large studies in the United States on de novo HD: 3,245 cases from the Surveillance, Epidemiology, and End Results (SEER) and 1,140 from Stanford University. The analysis of the two groups showed statistically significant differences (p<0.001) in the percentage of all histological types and odds ratios (OR) of the pooled effect of 0.4 (95% CI: 0.3-0.6) for lymphocyte predominance (LP), 0.3 (95% CI: 0.2-0.4) for nodular sclerosis (NS), 3.2 (95% CI: 2.6-3.8) for mixed cellularity (MC), and 6.3 (95% CI: 4.5-8.8) for lymphocyte depletion (LD). Comparison with the Stanford University series yielded similar results. Whilst retrospective and based on a limited number of cases, our data confirm a higher incidence of unfavorable histological subtypes in HIV-infected patients and show a reduction in the observed cases of good prognosis subtypes. Prospective studies, with careful histological observations, are required to better evaluate the characteristics of the LP subtype in the special setting of HIV infection.


Assuntos
HIV , Doença de Hodgkin/classificação , Doença de Hodgkin/virologia , Linfoma Relacionado a AIDS/epidemiologia , Doença de Hodgkin/epidemiologia , Humanos , Incidência , Linfoma Relacionado a AIDS/patologia , Prognóstico , Estudos Retrospectivos
19.
Ann Neurol ; 49(3): 362-6, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11261511

RESUMO

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb-onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical dystonia Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was characterized by prominent cranial-cervical and upper limb involvement and mild severity. A genome-wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667.


Assuntos
Cromossomos Humanos Par 1/genética , Distúrbios Distônicos/genética , Ligação Genética/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Haplótipos , Humanos , Itália , Escore Lod , Masculino , Linhagem
20.
Am J Hum Genet ; 68(4): 895-900, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11254447

RESUMO

The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In > or = 50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32-48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1. This region contains a novel locus for autosomal recessive early-onset parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199.


Assuntos
Cromossomos Humanos Par 1/genética , Genes Recessivos/genética , Ligação Genética/genética , Ligases , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/genética , Ubiquitina-Proteína Ligases , Adulto , Idade de Início , Mapeamento Cromossômico , Feminino , Heterogeneidade Genética , Marcadores Genéticos/genética , Haplótipos/genética , Homozigoto , Humanos , Itália , Escore Lod , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/fisiopatologia , Linhagem , Fenótipo , Proteínas/genética
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