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M H Polymeropoulos

Publications and source records attributed to M H Polymeropoulos.

At least 19 recordsLinked to original sources
PubMed2001

Mutation screening of the Wolfram syndrome gene in psychiatric patients.

Wolfram syndrome, a rare autosomal recessive neurodegenerative disorder, was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. It was later demonstrated that Wolfram syndrome patients were highly prone to psychiatric disorders. Mutations in exon 8 of the Wolfram syndrome gene account for 88% of the patients with Wolfram syndrome. To examine whether the gene responsible for causing Wolfram syndrome is involved in psychiatric disorders, we screened exon 8 of the Wolfram syndrome gene for mutations in 119 patients with schizophrenia, one patient with schizoaffective disorder, 12 patients with bipolar disorder and 15 patients with major depression, using sequence analysis. In Wolfram syndrome patients, this gene has been shown to have primarily nonsense or frameshift mutations, which would result in a premature truncation of the protein. None of the psychiatric patients screened in this study carried these types of mutations. We identified, however, 24 new variations whose significance remains to be determined.

Bipolar Disorder↗
PubMed2001

Genes that co-cluster with estrogen receptor alpha in microarray analysis of breast biopsies.

The estrogen receptor plays a critical role in the pathogenesis and clinical behavior of breast cancer. To better understand the molecular basis of estrogen-dependent forms of this disease we studied gene expression profiles from 53 primary breast cancer biopsies. Gene expression data for more than 7000 genes were generated from each tumor sample with oligo microarrays. A standard correlation-clustering algorithm identified 18 genes that co-clustered with estrogen receptor alpha. Eleven of these genes had previously been associated with estrogen regulation or breast tumorigenesis including trefoil factor 1 and estrogen regulated LIV-1. Additional study of these 18 genes may further delineate the role of estrogen receptor in breast cancer, generate new predictive biomarkers for response to endocrine therapies and identify novel therapeutic targets.

Animals↗
PubMed2001

Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element.

The human alpha-synuclein gene (SNCA) encodes a presynaptic nerve terminal protein that was originally identified as a precursor of the non-beta-amyloid component of Alzheimer's disease plaques. More recently, mutations in SNCA have been identified in some cases of familial Parkinson's disease, presenting numerous new areas of investigation for this important disease. Molecular studies would benefit from detailed information about the long-range sequence context of SNCA. To that end, we have established the complete genomic sequence of the chromosomal regions containing the human and mouse alpha-synuclein genes, with the objective of using the resulting sequence information to identify conserved regions of biological importance through comparative sequence analysis. These efforts have yielded approximately 146 and approximately 119 kb of high-accuracy human and mouse genomic sequence, respectively, revealing the precise genetic architecture of the alpha-synuclein gene in both species. A simple repeat element upstream of SNCA/Snca has been identified and shown to be necessary for normal expression in transient transfection assays using a luciferase reporter construct. Together, these studies provide valuable data that should facilitate more detailed analysis of this medically important gene.

Animals↗
PubMed2001

Clinical phenotype in patients with alpha-synuclein Parkinson's disease living in Greece in comparison with patients with sporadic Parkinson's disease.

OBJECTIVE: An Ala53Thr mutation of the alpha-synuclein gene has been recently identified as a rare cause of autosomal Parkinson's disease (PD). The clinical characteristics of 15 patients with PD living in Greece with the Ala53Thr alpha-synuclein mutation (alpha-synPD) were compared with patients with sporadic Parkinson's disease (sPD). METHODS: An investigator, blind to the results of the genetic analysis, examined 15 patients with alpha-synPD and 52 consecutive patients with sPD. Demographic data, age at onset of the illness, modality of presentation, and duration of PD were collected. The unified Parkinson's disease rating scale, the Hoehn and Yahr scale, and the Schwab-England scale were completed. The patients with alpha-synPD were matched for duration of disease with 32 of the 52 patients with sporadic PD (MsPD group). RESULTS: Patients with the alpha-synuclein mutation were significantly younger (mean 7.6 years), showed the first sign of the disease significantly earlier in life (mean 10.8 years), and had significantly longer duration of the disease compared with patients with sPD. Tremor at onset of the disease was present in only one (6.7%) of the patients with alpha-synPD, whereas it was present in 32 (61.5%) of the patients with sPD (p=0.0006). During the course of the disease one patient in the alpha-synPD group went on to develop tremor compared with six patients in the sPD group. Rigidity, bradykinesia, postural instability, orthostatic hypotension, intellectual impairment, depression, complications of therapy, and clinical severity of the disease at the time of examination did not differ significantly between patients with alpha-synPD and those with sPD, or between patients with alpha-synPD and the MsPD group. CONCLUSION: The younger age at onset of the illness, the much lower prevalence of tremor, and the longer duration of the disease characterise the clinical phenotype in this sample of patients with alpha-synPD. The other symptoms and signs of the illness did not seem to differentiate the patients with alpha-synPD from those with sPD.

Adult↗
PubMed2001

The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease.

A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.

Adult↗
PubMed2000

Alpha-synuclein immunoreactivity of huntingtin polyglutamine aggregates in striatum and cortex of Huntington's disease patients and transgenic mouse models.

Polyglutamine expansions in proteins are implicated in at least eight inherited neurodegenerative disorders, including Huntington's disease. These mutant proteins can form aggregates within the nucleus and processes of neurons possibly due to misfolding of the proteins. Polyglutamine aggregates are ubiquitinated and sequester molecular chaperone proteins and proteasome components. To investigate other protein components of polyglutamine aggregates, cerebral cortex and striata from patients with Huntington's disease and full-length cDNA transgenic mouse models for this disease were examined immunohistochemically for alpha-synuclein reactivity. Our findings demonstrate that alpha-synuclein can be used as a marker for huntingtin polyglutamine aggregates in both human and mice. Moreover in the HD transgenic mice, the intensity of immunoreactivity increases with age. The significance of recruitment of alpha-synuclein into huntingtin aggregates and its translocation away from the synapses remains to be determined. We propose that aberrant interaction of mutant huntingtin with other proteins, including alpha-synuclein, may influence disease progression.

Amino Acid Motifs↗
PubMed2000

Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.

Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions.

Alternative Splicing↗
PubMed2000

Genetics of Parkinson's disease.

Several genetic factors have been recently recognized as related to the etiology of Parkinson's disease. Mutations in the genes coding for alpha-synuclein and ubiquitin carboxy-terminal hydrolase have been identified in families with autosomal dominant Parkinson's disease. Mutations in the Parkin gene are responsible for autosomal recessive parkinsonism. These first pieces of the molecular puzzle of Parkinson's disease offer novel insights into the pathophysiology of the illness.

Chromosome Mapping↗
PubMed1999

Genomic structure and localization of the human protein phosphatase 2A BRgamma regulatory subunit.

In the course of our analysis of genomic sequence from the human chromosome 4p16.1 region harboring both the Wolfram and Ellis van Creveld syndrome genes we have identified a sequence with high homology (98% at the amino acid level) to the rat cDNA coding for the protein phosphatase 2A BRgamma (PP2ABRgamma) regulatory subunit. Although the human cDNAs for both the BRalpha and BRbeta isoforms have been described previously, the BRgamma subunit has not yet been identified in humans. Here we describe the precise genomic organization and genetic localization of the human PP2ABRgamma gene.

Amino Acid Sequence↗
PubMed1999

The genexpress IMAGE knowledge base of the human muscle transcriptome: a resource of structural, functional, and positional candidate genes for muscle physiology and pathologies.

Sequence, gene mapping, and expression data corresponding to 910 genes transcribed in human skeletal muscle have been integrated to form the muscle module of the Genexpress IMAGE Knowledge Base. Based on cDNA array hybridization, a set of 14 transcripts preferentially or specifically expressed in muscle have been selected and characterized in more detail: Their pattern of expression was confirmed by Northern blot analysis; their structure was further characterized by full-insert cDNA sequencing and cDNA extension; the map location of the corresponding genes was refined by radiation hybrid mapping. Five of the 14 selected genes appear as interesting positional and functional candidate genes to study in relation with muscle physiology and/or specific orphan muscular pathologies. One example is discussed in more detail. The expression profiling data and the associated Genexpress Index2 entries for the 910 genes and the detailed characterization of the 14 selected transcripts are available from a dedicated Web server at. The database has been organized to provide the users with a working space where they can find curated, annotated, integrated data for their genes of interest. Different navigation routes to exploit the resource are discussed.

Base Sequence↗
PubMed1998

Genomic organization and localization of the human CRMP-1 gene.

The Collapsin Response Mediator Protein-1 (CRMP-1) is a brain specific protein considered to be involved in the collapsin-induced growth cone collapse during neural development. CRMP-1 belongs to the Unc-33 gene family. Here we report the genomic structure and the localization of the human CRMP-1 gene to chromosome 4p16.1. Sequence analysis revealed that the human CRMP-1 gene consists of 14 exons. We have also established sequencing assays for all its coding exons. This should permit the rapid screening for mutations to assess CRMP-1 role in genetic disorders mapped in the 4p16.1 region.

Chromosome Mapping↗
PubMed1998

Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.

Adenocarcinoma↗
PubMed1998

Genomic organization and expression of the human beta-synuclein gene (SNCB).

The beta-synuclein protein is highly homologous to the alpha-synuclein protein for which two mutations were reported in some familial cases of Parkinson disease. It has been shown that both alpha- and beta-synucleins may be able to inhibit phospholipase D2 selectively. We have observed that the beta-synuclein gene (HGMW-approved symbol, SNCB) is highly expressed in brain including the substantia nigra, the main region of neuronal degeneration in patients with Parkinson disease. We have determined the intron-exon structure of the beta-synuclein gene and established sequencing assays that will facilitate the search for mutations in the beta-synuclein gene in patients with Parkinson disease or other neurodegenerative disorders.

Amino Acid Sequence↗
PubMed1998

A physical map of 30,000 human genes.

A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.

Animals↗