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P Maciel

Publications and source records attributed to P Maciel.

At least 19 recordsLinked to original sources
PubMed2006

APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.

BACKGROUND: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. METHODS: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. RESULTS: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96-1.34 and OR 0.89, 95% CI 0.78-1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. CONCLUSION: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Alleles↗
PubMed2006

Chromatin remodeling and neuronal function: exciting links.

Regulation of gene expression occurs at different levels, from DNA to protein, and through various mechanisms. One of them is modification of the chromatin structure, which is involved in the definition of transcriptional active and inactive regions of the chromosomes. These phenomena are associated with reversible chemical modifications of the genetic material rather than with variability within the DNA sequences inherited by the individual and are therefore called 'epigenetic' modifications. Ablation of the molecular players responsible for epigenetic modifications often gives rise to neurological and behavioral phenotypes in humans and in mouse models, suggesting a relevant function for chromatin remodeling in central nervous system function, particularly in the adaptive response of the brain to stimuli. We will discuss several human disorders that are due to altered epigenetic mechanisms, with special focus on Rett syndrome.

Adaptation, Physiological↗
PubMed2005

Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal.

OBJECTIVE: To gain insights on the molecular mechanisms of mutation that led to the emergence of expanded alleles in the MJD gene, by studying the behavior of wild-type alleles and testing the association of its distribution with the representation of the disease. METHODS: The number of CAG motifs in the MJD gene was determined in a representative sample of 1000 unrelated individuals. Associations between the repeat size and the epidemiological representation of MJD were tested. RESULTS: The allelic profile of the total sample was in the normal range (13-41 repeats), with mode (CAG)23. No intermediate alleles were present. Allelic size distribution showed a negative skew. The correlation between the epidemiological representation of MJD in each district and the frequency of small, medium and large normal alleles was not significant. Further correlations performed grouping the districts also failed to produce significant results. CONCLUSIONS: The absence of association between the size of the repeats and the representation of MJD demonstrates that prevalence is not an indirect reflection of the frequency of large normal alleles. Globally the results obtained are in accordance with a model that postulates the occurrence of a few mutations on the basis of most of the MJD cases worldwide.

Ataxin-3↗
PubMed2005

Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement.

The authors identified a missense mutation in the FTL gene (474G>A; A96T) in a 19-year-old man with parkinsonism, ataxia, corticospinal signs, mild nonprogressive cognitive deficit, and episodic psychosis. This mutation was also present in his asymptomatic mother and younger brother, who had abnormally low levels of ferritin in the serum. The patient and his mother displayed bilateral involvement of the pallidum.

Adult↗
PubMed2003

A whole genome screen for association with multiple sclerosis in Portuguese patients.

Multiple sclerosis (MS) is common in Europe affecting up to 1:500 people. In an effort to identify genes influencing susceptibility to the disease, we have performed a population-based whole genome screen for association. In this study, 6000 microsatellite markers were typed in separately pooled DNA samples from MS patients (n=188) and matched controls (n=188). Interpretable data was obtained from 4661 of these markers. Refining analysis of the most promising markers identified 10 showing potential evidence for association.

Adolescent↗
PubMed2002

[Rett's syndrome. Clinical features and advances in genetics].

INTRODUCTION: Rett's syndrome (RS) is a disorder of neurological development which is the second commonest cause of mental retardation in girls. It is normally caused by de novo mutations of a gene on the X chromosome. This gene encodes for the protein joining the methyl CpG (MECP2). Mutations of this gene have been found in approximately 80% of the cases confirmed as having the classical form of RS. Mutations of the gene MECP2 were also found in about a third of the nonclassical cases of RS and in other conditions: women with mild or severe mental retardation, children with autism, even children with neonatal encephalopathy or with a clinical condition similar to RS. DEVELOPMENT: Studies correlating the genotypes and phenotypes in classical RS suggest that the pattern of inactivation of the X chromosome is more important in determining the severity of the condition than the type or site of the mutation. However, when we consider all the phenotypes associated with mutations of MECP2, it is seen that the type of mutation correlates to a certain degree with the clinical onset and severity of the disorder. CONCLUSIONS: Recent advances in the genetics of RS therefore have specific application in the clinical field. They give further markers for diagnosis and possibly indicate the prognosis, as well as being useful in genetic counselling for the families of patients with RS.

Child↗
PubMed2001

Improvement in the molecular diagnosis of Machado-Joseph disease.

BACKGROUND: Direct detection of the gene mutation allows for the confirmation of the clinical diagnosis of Machado-Joseph disease (MJD), the most frequent cause of autosomal dominant spinocerebellar ataxia worldwide. OBJECTIVE: To address the main difficulties in our national MJD predictive testing program. The first was the emergence of intermediate alleles, for which it is not yet possible to determine whether they will cause disease. The second was the issue of homoallelism, ie, homozygosity for 2 normal alleles with exactly the same (CAG)(n) length, which occurs in about 10% of all test results. METHODS: A large pedigree with 1 affected patient carrying a 71 and a 51 CAG repeat and 2 asymptomatic relatives carrying the 51 CAG repeat and normal-size alleles underwent clinical and molecular studies. Intragenic haplotypes for these alleles were determined. A representative sample of the healthy population in the region was obtained to assess the distribution of the normal (CAG)(n) length. We established the genotype for 4 intragenic polymorphisms in the gene for MJD (MJD1) in 21 homoallelic individuals, to distinguish their 2 normal chromosomes. In addition, we developed a new Southern blot method to completely exclude cases of nonamplification of expanded alleles in the homoallelic individuals. RESULTS: The study of the family in which the 51 CAG repeat was found suggests that the allele is apparently not associated with disease. These intermediate alleles were not present in a large sample of the healthy population from the same region. Intragenic polymorphisms allowed distinction of the 2 different normal alleles in all cases of homoallelism. The absence of an expanded allele was also confirmed by Southern blot. CONCLUSIONS: We propose an improved protocol for molecular testing for MJD. These strategies, developed to overcome the practical difficulties mostly in the presymptomatic and prenatal diagnosis of MJD, should prove useful for other polyglutamine-related disorders.

Adult↗
PubMed2001

The genomic structure and expression of MJD, the Machado-Joseph disease gene.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder that is clinically characterized by cerebellar ataxia and various associated symptoms. The disease is caused by an unstable expansion of the CAG repeat in the MJD gene. This gene is mapped to chromosome 14q32.1. To determine its genomic structure, we constructed a contig composed of six cosmid clones and eight bacterial artificial chromosome (BAC) clones. It spans approximately 300kb and includes MJD. We also determined the complete sequence (175,330bp) of B445M7, a human BAC clone that contains MJD. The MJD gene was found to span 48,240bp and to contain 11 exons. Northern blot analysis showed that MJD mRNA is ubiquitously expressed in human tissues, and in at least four different sizes; namely, 1.4, 1.8, 4.5, and 7.5kb. These different mRNA species probably result from differential splicing and polyadenylation, as shown by sequences of the 21 independent cDNA clones isolated after the screening of four human cDNA libraries prepared from whole brain, caudate, retina, and testis. The sequences of these latter clones relative to the MJD gene in B445M7 indicate that there are three alternative splicing sites and eight polyadenylation signals in MJD that are used to generate the differently sized transcripts.

Alternative Splicing↗
PubMed2000

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Alleles↗
PubMed2000

High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles.

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.

Adolescent↗
PubMed1998

Restriction map of a YAC and cosmid contig encompassing the oculopharyngeal muscular dystrophy candidate region on chromosome 14q11.2-q13.

As part of our effort to clone positionally the oculopharyngeal muscular dystrophy (OPMD) gene, we constructed a YAC contig, a cosmid contig, and an EcoRI restriction map of the OPMD candidate region. The YAC contig spans more than 2 Mb and encompasses the loci D14S283 and D14S990 and the cardiac alpha and beta myosin heavy chain genes (MYH6 and MYH7). A 700-kb cosmid contig containing the D14S990 and the myosin genes and a long-range restriction map covering the region between D14S990 and the MYH6 and MYH7 gene cluster were established. A detailed EcoRI restriction map of the cosmid contig was determined, and five putative CpG islands were identified. Based on these data, the four loci were mapped within an approximately 600-kb region with the following centromere to telomere order: D14S283, D14S990, MYH6, and MYH7. The YAC and cosmid contigs will facilitate the identification of genes lying within the OPMD candidate interval.

Chromosome Walking↗
PubMed1998

Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families.

The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes.

Adolescent↗
PubMed1998

Prenatal diagnosis of Machado-Joseph disease by direct mutation analysis.

MJD is the most frequent dominant ataxia and an incapacitating disorder. Onset is most frequently during the reproductive years, and genetic counseling is its only means of prevention. The causative mutation--an expansion of a (CAG)n on chromosome 14q32.1--can now be directly detected. We now report the first two cases of prenatal diagnosis (PND). The first presented as a simultaneous request for predictive testing and PND at 14 weeks of pregnancy. Owing to time constraints, we performed a full protocol of counseling with shorter inter between sessions, while psycho-social evaluation of the other parent obstetric consults were also begun. We ensured that the couple wished termination if the fetus was a carrier, to avoid a presymptomatic test for the unborn child. We were thus able to deliver test results two weeks before PND. As the fetus carried an expanded allele (77 CAGs) inherited from his father, termination was performed and the couple received counselling, psychological and social support. The second case was the fetus of a carrier-mother that was diagnosed as non-carrier, also after amniocentesis.

Adult↗
PubMed1997

Machado-Joseph disease gene products carrying different carboxyl termini.

Three cDNA clones for the Machado-Joseph disease gene (MJD1) were isolated, two of which have a new exon sequence and a distinct 3' terminal nucleotide sequence resulting in a new carboxyl terminal domain in the translated product. The nucleotide sequence of the other one is similar to the previously published one except for five polymorphisms, one of which is a single nucleotide substitution resulting in a change from the stop codon (TAA; allele A) to a tyrosine residue (TAC; allele C). Genetic analysis results suggest that Japanese MJD mutations are associated with allele A.

Amino Acid Sequence↗
PubMed1996

No association between chromosome-18 markers and lithium-responsive affective disorders.

An allelic association study of excellent responders to lithium was conducted with a candidate gene (Golf, a G-protein receptor gene) and five other chromosome-18p markers. Golf is of special interest because it maps to a region of chromosome 18 where two independent groups (Berrettini et al., 1994; Stine et al., 1995) have found linkage to bipolar disorder. It has been proposed that G proteins are involved in the pathogenesis of bipolar disorder, and lithium, an effective prophylactic agent, is known to impair G-protein activation. To reduce heterogeneity--a common obstacle to genetic investigation--only patients who showed excellent response to lithium prophylaxis were studied. Fifty-five genetically unrelated excellent responders to lithium prophylaxis were compared with 94 normal subjects of similar ethnic background. The groups did not differ in either allele or genotype frequency for the tested markers. The data do not support the hypothesis that the tested loci confer a major susceptibility for affective disorders.

Adult↗
PubMed1996

Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease.

BACKGROUND: Machado-Joseph disease (MJD) is a type of autosomal dominant spinocerebellar ataxia for which molecular diagnosis is available. We identified 4 families segregating the MJD mutation in which no unequivocal clinical diagnosis could be established prior to molecular testing. Ethnic background, clinical, and molecular characteristics of 19 individuals carrying the MJD mutation in these 4 families were compared with a group of 32 Portuguese families who were clinically diagnosed as having MJD and were found to carry the MJD mutation. RESULTS: Several factors seemed to have an impact in the accuracy of the clinical diagnosis, such as ethnic origin; the number of affected individuals available for examination in each family; the absence of patients showing specific clinical features, such as extrapyramidal signs; and the size of the expanded CAG repeat in the MJD gene. CONCLUSION: Since the recognition of MJD based solely on clinical grounds might sometimes be misleading, a search for the MJD mutation should be performed in patients with a clinical diagnosis of spinocerebellar degeneration.

Adult↗