Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene for autosomal recessive juvenile Parkinsonism (AR-JP) recently has been mapped to chromosome 6q25.2-27 in Japanese families. We have tested one Algerian and 10 European multiplex families with early-onset Parkinson disease for linkage to this locus, with marker D6S305. Homogeneity analysis provided a conditional probability in favor of linkage of >.9 in eight families, which were analyzed further with eight microsatellite markers spanning the 17-cM AR-JP region. Haplotype reconstruction for eight families and determination of the smallest region of homozygosity in two consanguineous families reduced the candidate interval to 11.3 cM. If the deletion of two microsatellite markers (D6S411 and D6S1550) that colocalize on the genetic map and that segregate with the disease in the Algerian family is taken into account, the candidate region would be reduced to <1 cM. These findings should facilitate identification of the corresponding gene. We have confirmed linkage of AR-JP, in European families and in an Algerian family, to the PARK2 locus. PARK2 appears to be an important locus for AR-JP in European patients. The clinical spectrum of the disease in our families, with age at onset <=58 years and the presence of painful dystonia in some patients, is broader than that reported previously.
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PMID:Chromosome 6-linked autosomal recessive early-onset Parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. The French Parkinson's Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson's Disease. 963 31

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.
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PMID:A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. 1007 23

Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.
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PMID:Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. 1088 78

A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early-onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult-onset, clinically typical tremor-dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinson's disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa-induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late-onset typical Parkinson's disease.
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PMID:Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. 1089 17

Autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF, syn. autosomal recessive juvenile parkinsonism, PARK2) is one of the hereditary parkinsonian syndromes. We examined subjects consisting of 43 patients from 22 families with AR-EPDF. The clinical features were relatively homogeneous, including the average age at onset of 26.1 years, beginning with dystonic gait disturbance, diurnal fluctuation of the symptoms (sleep benefit) unrelated to medication, dystonia (mainly foot dystonia), hyperactive tendon reflex, remarkable effect of levodopa and other antiparkinsonism drugs, susceptibility to dopa-induced dyskinesia, mild autonomic symptoms, absence of dementia, and slow progression of disease. Some patients had hysteric character or psychic symptoms provoked by medication. Pathologic study revealed neuronal loss in the substantia nigra pars compacta and locus coeruleus without Lewy body formation. We performed extensive molecular genetic analysis of the parkin gene in 16 families to identify a total of six different deletional mutations. In AR-EPDF loss of newly discovered 'Parkin' protein is responsible for selective degeneration of the pigmented neurons in the substantia nigra and locus coeruleus. Compared with autosomal dominant Parkinson's disease, AR-EPDF appears to be more prevalent and present in several ethnic groups.
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PMID:Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification. 1098 66

A genetic contribution to the etiology of Parkinson's disease was first suspected by Charcot and later confirmed by case control, family, and twin studies, as well as by the description of large parkinsonian families with Mendelian inheritance of the disease. Recent progress in the field of molecular neurogenetics has led to the identification of several Parkinson disease genes and gene loci. Mutations in the alpha-Synuclein gene (PARK1) and in the gene for the ubiquitin C-terminal hydrolase I (PARK5), along with two gene loci harboring currently unknown genes (PARK3 and PARK4), have been linked to very rare autosomal dominantly inherited parkinsonian syndromes. Mutations in the parkins gene (PARK2), causing autosomal recessive early-onset parkinsonism, are much more common and therefore of clinical relevance. A second gene locus for an autosomal dominantly inherited Parkinsonian syndrome was recently localized on chromosome 1 (PARK6). All three parkinson genes identified thus far imply the involvement of the ubiquitin pathway of protein degradation in the pathogenesis of Parkinson's disease.
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PMID:[The genetics of Parkinson syndrome]. 1144 21

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.
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PMID:[Gene diagnosis of Alzheimer's disease and Parkinson's disease]. 1245 76

Autosomal recessive, early onset parkinsonism (AREP) is genetically heterogeneous. Mutations in the parkin gene (PARK2 locus, chromosome 6q) account for up to 50% of AREP families. The parkin protein displays ubiquitin-ligase activity for different targets, which accumulate in the brain of patients with parkin defect and might cause neurodegeneration. Two new AREP loci (PARK6 and PARK7) have been recently mapped on chromosome 1p and confirmed in independent datasets, suggesting that both might be frequent. The three AREP forms display similar clinical phenotypes. Recruiting new families will help cloning the defective genes at PARK6 and PARK7 loci. This will contribute to unraveling the pathogenesis of AREP, and it is also expected to foster our understanding of molecular events underlying classic Parkinson's disease.
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PMID:Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7. 1254 43

A method for analysis of deletions and duplications of individual exons and groups of exons in the parkin gene (PARK2) in both homozygous and heterozygous states has been developed. The method is based on semiquantitative polymerase chain reaction (PCR). The method has been used for analysis of the frequency of deletions in gene PARK2 in patients with idiopathic Parkinson's disease from Bashkortostan. Two unrelated patients have been found to carry a deletion of the 12th (last) exon of gene PARK2. Possibly, this deletion has caused the disease in the given patients.
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PMID:[Analysis of deletion mutations in the PARK2 gene in idiopathic Parkinson's disease]. 1266 18

Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an alpha-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.
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PMID:Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. 1276 Oct 37


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