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M H Polymeropoulos

Publications and source records attributed to M H Polymeropoulos.

At least 37 records · Page 2Linked to original sources
PubMed1998

Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body's ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver's ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore throw light on regulation of net dietary cholesterol absorption and lead to an advancement in the management of this important cardiovascular risk factor. By studying 10 well-characterized families with this disorder, we have localized the genetic defect to chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lodscore 4.49, theta = 0.0).

Cardiovascular Diseases↗
PubMed1998

Contig map of the Parkinson's disease region on 4q21-q23.

We have constructed a yeast artificial chromosome contig (YAC) map of human chromosome 4q21-q23 across the Parkinson's disease region by combining molecular and fluorescence in situ hybridization techniques. This map contains 55 YACs and 51 molecular markers, including 23 polymorphic markers. We have also isolated one P1 and 33 bacterial artificial chromosomes located within this contig. Plasmid libraries were generated from 11 of these BAC and P1 clones, and 614 random plasmid clones were sequenced for a total of about 200 kb. This contig allowed us to precisely determine the location of 18 transcripts within the D4S2460-D4S2986 interval, including the alpha-synuclein gene found to be mutated in some families with Parkinson's disease.

Chromosome Mapping↗
PubMed1998

Autosomal dominant Parkinson's disease and alpha-synuclein.

Multiple factors have been hypothesized over the years to be contributory and/or causative for Parkinson's disease (PD). Hereditary factors, although originally discounted, have recently emerged in the focus of PD research. The study of a large Italian family with PD using a genome scan approach led to the mapping of a PD susceptibility gene to the 4q21-q23 genomic region, where the gene for alpha-synuclein was previously mapped. Mutation analysis of the alpha-synuclein in four unrelated families with PD revealed a missense mutation segregating with the illness. Alpha-synuclein is an abundant presynaptic protein in the human brain with unknown function. It is conceivable that the mutation identified in the PD families may result in self-aggregation and/or decreased degradation of the protein, leading to the development of intracytoplasmic inclusion bodies and eventually to neuronal cell death. Moreover, the discovery of a mutation in the synuclein gene may offer us new insights in the understanding of the pathways that lead to neuronal degeneration.

Chromosome Mapping↗
PubMed1998

Autosomal dominant Parkinson's disease.

Multiple factors have been hypothesized over the years to be contributory and or causative for Parkinson's disease (PD). Hereditary factors, although originally discounted, have recently emerged in the focus of PD research. The study of a large Italian family with PD using a genome scan approach led to the mapping of a PD susceptibility gene to the 4q21-q23 genomic region, where the gene for alpha-synuclein was previously mapped. Mutation analysis of the alpha-synuclein in four unrelated families with PD revealed a missense mutation segregating with the illness. Alpha-synuclein is an abundant presynaptic protein of the human brain of unknown function. It is conceivable that the mutation identified in the PD families may result in self-aggregation and or decreased degradation of the protein, leading to the development of intracytoplasmic inclusion bodies and eventually to neuronal cell death. Moreover, the discovery of a mutation in the synuclein gene may offer us new insights into the understanding of the pathways that lead to neuronal degeneration.

Cell Death↗
PubMed1998

Identification, localization and characterization of the human gamma-synuclein gene.

We have identified and characterized a new member of the human synuclein gene family, gamma-synuclein (SNCG). This gene is composed of five exons, which encode a 127 amino acid protein that is highly homologous to alpha-synuclein, which is mutated in some Parkinson's disease families, and to beta-synuclein. The gamma-synuclein gene is localized to chromosome 10q23 and is principally expressed in the brain, particularly in the substantia nigra. We have determined its genomic sequence, and established conditions for sequence analysis of each of the exons. The gamma-synuclein gene, also known as BCSG1, was recently found to be overexpressed in advanced infiltrating carcinoma of the breast. Our survey of the EST database indicated that it might also be overexpressed in an ovarian tumor.

Adult↗
PubMed1998

Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease.

Female↗
PubMed1998

Predisposition of Wolfram syndrome heterozygotes to psychiatric illness.

Identification of specific genes that predispose to psychiatric illness will lead to more precise psychiatric diagnosis and more effective treatment. Heterozygous carriers of genes for many autosomal recessive syndromes may be 1% or more of the general population. Thus, if mutations at a specific locus produce psychiatric manifestations in homozygous affected individuals, it is important to determine whether mutations at such a locus also predispose heterozygous carriers to psychiatric disorders. The hypothesis that heterozygous carriers of the gene for the Wolfram syndrome (WS) are predisposed to psychiatric illness was supported previously by the finding of an excess of psychiatric hospitalizations and suicides in WS blood relatives compared to spouse controls. This hypothesis has now been tested further by comparing the number of psychiatrically hospitalized blood relatives with the specific marker haplotype associated with the Wolfram syndrome gene in their families to the number expected under the null hypothesis, calculated from Mendelian inheritance principles and the estimated haplotype frequency. The proportion of psychiatrically hospitalized relatives who were WS carriers (10/11) was much higher than expected (3.1/11), leading to the provisional estimate that WS gene carriers are 26-fold more likely to require psychiatric hospitalization than non-carriers.

Adult↗
PubMed1998

Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease.

A missense mutation in the human alpha synuclein gene was recently identified in some cases of familial Parkinson's disease (FPD). We have developed an antibody that recognizes the C-terminal 12 amino acids of the human alpha synuclein protein and have demonstrated that alpha synuclein is an abundant component of the Lewy bodies found within the degenerating neurons of patients with Parkinson's disease (PD). The presence of alpha synuclein in Lewy bodies of sporadic PD patients suggests a central role for alpha synuclein in the pathogenesis of PD.

Aged↗
PubMed1998

The gene for glycogen-storage disease type 1b maps to chromosome 11q23.

Glycogen-storage disease type 1 (GSD-1), also known as "von Gierke disease," is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase) activity. There are four distinct subgroups of this autosomal recessive disorder: 1a, 1b, 1c, and 1d. All share the same clinical manifestations, which are caused by abnormalities in the metabolism of glucose-6-phosphate (G6P). However, only GSD-1b patients suffer infectious complications, which are due to both the heritable neutropenia and the functional deficiencies of neutrophils and monocytes. Whereas G6Pase deficiency in GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, indicating a separate locus for the disorder in the 1b subgroup. We now report the linkage of the GSD-1b locus to genetic markers spanning a 3-cM region on chromosome 11q23. Eventual molecular characterization of this disease will provide new insights into the genetic bases of G6P metabolism and neutrophil-monocyte dysfunction.

Chromosome Deletion↗
PubMed1997

Mapping of the gene (NRAP) encoding N-RAP in the mouse and human genomes.

N-RAP is a nebulin-related actin-binding protein found at the myotendon junction in skeletal muscle and at the intercalated disks in cardiac muscle. We mapped the NRAP gene to mouse chromosome 19 using interspecific crosses and to human chromosome 10 using radiation hybrid panels. Comparative analysis of the mouse and human genomes indicates that the NRAP gene is located in regions of conserved synteny between the two species.

Animals↗
PubMed1997

Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.

Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.

Amino Acid Sequence↗
PubMed1997

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Age of Onset↗
PubMed1997

Evidence for a new spinocerebellar ataxia locus.

The autosomal dominant ataxias (ADA) are a diverse group of multisystem, neurodegenerative disorders characterized by mutations at several chromosomal loci (SCA types 1-5, SCA type 7, DRPLA). We excluded all the known SCA loci by mutational and linkage analyses is an American family of British origin with ADA and document that an additional ataxia locus must exist. The clinical characteristics and ethnic origin of our family are similar to the British Drew family of Walworth with the SCA type 3 mutation and differ from other families without a known ataxia locus. Individuals in our family and the Drew family initially show signs of ataxia but may develop variable degrees of ophthalmoplegia, Parkinsonian features and central demyelination. The phenotypic diversity in families without a known ataxia locus suggests that there may be several other undefined ataxia loci.

Adolescent↗
PubMed1997

C2H2-171: a novel human cDNA representing a developmentally regulated POZ domain/zinc finger protein preferentially expressed in brain.

We describe a novel human zinc finger cNDA. C2H2-171. This cDNA represents an mRNA which encodes a protein of 484 amino acids and a calculated molecular weight of 54 kD. Four zinc finger-like domains are found in the C-terminal end of the protein. At the N-terminus, C2H2-171 contains a POZ/tramtrack-like domain similar to that found in the tumor associated zinc finger proteins LAZ-3/BCL-6 and PLZ-F, as well as in non-zinc finger proteins. C2H2-171 RNA is preferentially expressed in the brain, and increases during the course of murine development, with maximal expression in the adult. C2H2-171 RNA is differentially expressed in brain regions, with the highest level of expression in the cerebellum. C2H2-171 RNA was expressed at high levels in primary cerebellar granule cell neurons compared to astrocytes. The gene encoding C2H2-171 is highly conserved in vertebrates, and maps to the terminus of human chromosome 1 (1q44-ter). This chromosomal location is associated with a number of cytogenetic aberrations including those involving brain developmental anomalies and tumorigenesis. These data suggest that C2H2-171 may play an important role in vertebrate brain development and function.

Amino Acid Sequence↗