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Biomedical subjects

H Matsumine

Publications and source records attributed to H Matsumine.

At least 19 recordsLinked to original sources
PubMed2001

Parkin gene causing benign autosomal recessive juvenile parkinsonism.

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset parkinsonism caused by exonic deletions or point mutations in the parkingene. The relationship between the type of the genetic defect and the clinical presentation, the response to therapy, and the evolution have not been yet determined. The authors describe a single-basepair deletion at nucleotide 202 in exon 2 of the parkin gene in a kindred with a benign clinical course.

Adolescent↗
PubMed2001

Familial Parkinson's disease. Alpha-synuclein and parkin.

We have reviewed recent progress in establishing the function of alpha-synuclein and parkin in relation to nigral degeneration in autosomal dominant and autosomal recessive PD. Mutations of alpha-synuclein (Ala53Thr and Ala30Pro) cause a form of autosomal dominant PD with early onset. Parkin is a novel protein expressed in the cytoplasm, including the terminal regions and Golgi apparatus. Mutations of parkin cause a form of autosomal recessive young-onset PD (ARJP). Both proteins appear to be associated with fast axonal transport. In addition, in sporadic PD, normal alpha-synuclein shows an increased tendency to self-aggregate. Thus, altered axonal transport of presynaptic proteins appears to play a crucial role in neurodegeneration in PD.

Humans↗
PubMed2000

Exonic deletion mutations of the Parkin gene among sporadic patients with Parkinson's disease.

Exonic deletions of the Parkin gene are common in the autosomal recessive form of juvenile parkinsonism. Here we report Parkin gene mutations among apparently sporadic Parkinson's disease (PD) patients. We screened 200 patients with PD (103 women and 97 men). The age of onset was 54.2+/-10.3years (mean+/-S.D.).Four out of the 200 patients had homozygous exonic deletions in the Parkin gene. The clinical features of these four patients were essentially the same as those of idiopathic PD. The age of onset was consistently younger (33, 38, 47 and 48years, respectively). On medication, all of them were at Hoehn and Yahr stage II or III even after 12-16years from the onset of the disease.Thus 2% of apparently sporadic PD patients in Japan have homozygous Parkin gene mutations. This positive rate was 6.3% among the patients with the age of onset below 50. Our study suggests that the prevalence of the carrier state of Parkin gene may be more than that we expected. Our study warrants further studies on Parkin gene mutations in apparently sporadic PD patients.

Journal Article↗
PubMed2000

PARKIN as a pathogenic gene for autosomal recessive juvenile parkinsonism.

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Recently, we idenfied a novel gene named Parkin to be responsible for the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP). Various mutations were found in AR-JP patients of Japanese and other ethnic origins, providing a definitive evidence for the Parkin to be a causative gene for AR-JP. The predicted structure of Parkin protein and its mutation provide important clues for studying the functional role of the Parkin protein in leading to selective degeneration of nigral neurons in the brains of AR-JP patients.

Amino Acid Motifs↗
PubMed2000

Progress in the clinical and molecular genetics of familial parkinsonism.

Parkinson's disease (PD) is a neurodegenerative disease with clinical features resulting from deficiency of dopamine in the nigrostriatal system. Most PD cases are sporadic and the primary cause of the disease is still unknown. Recently, familial PD and parkinsonism have received much attention because these forms of the disease might provide clues to the genetic risk factors involved in the pathogenesis of idiopathic PD. To date, two causative genes, alpha-synuclein and the parkin gene, have been identified. alpha-Synuclein is involved in the pathogenesis of an autosomal dominant form of PD and constitutes a major component of the Lewy body, which is a pathological hallmark of idiopathic PD. In addition, mutations in the parkin gene have been identified as the cause of autosomal recessive juvenile parkinsonism (AR-JP). AR-JP manifests itself as a highly selective degeneration of the substantia nigra and the locus coeruleus, but without Lewy body formation. In addition to these two genes, four chromosomal loci have been linked to other forms of familial PD. Furthermore, there are a number of other pedigrees of familial PD in which linkage to known genetic loci has been excluded. Molecular cloning of these disease genes and elucidation of the function of their gene products will greatly contribute to our understanding of the pathogenesis of idiopathic PD.

Amino Acid Sequence↗
PubMed2000

Autosomal recessive early-onset parkinsonism with diurnal fluctuation: clinicopathologic characteristics and molecular genetic identification.

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.

Adolescent↗
PubMed1999

Autosomal-recessive juvenile parkinsonism in a Jewish Yemenite kindred: mutation of Parkin gene.

We report a Jewish family of Yemenite origin in which three brothers born from a consanguineous marriage had juvenile parkinsonism. The DNA samples from three affected brothers and one healthy brother were analyzed for the linkage to markers covering the autosomal-recessive juvenile parkinsonism (AR-JP) locus. A perfect homozygous cosegregation to the markers was found, giving a maximal lod score of 3.11 at D6S1579, D6S305, and D6S411, all of which are 0 cm apart from each other (nonparametric linkage score, 8.041; p = 0.000977). Exon 3 of the Parkin gene was homozygously deleted in all patients. The AR-JP gene also exists in the Jewish population.

DNA↗
PubMed1999

Polymorphism in the parkin gene in sporadic Parkinson's disease.

We report polymorphism of the parkin gene in 160 sporadic Parkinson's disease (PD) patients and controls. Three polymorphisms were found: a G-to-A transition in exon 4 (S/N167), a C-to-T transition in exon 10 (R/W366), and a G-to-C transition in exon 10 (V/L380). Genotype distributions and allele frequencies of S/N167 and V/L380 did not differ significantly between the two groups. The R/W366 allele frequency was significantly lower in PD patients (1.2 vs 4.4%). The level of protection from PD provided by this allele was 3.60 (95% CI; range, 0.45-6.50), suggesting that it may be a protective factor against PD.

Aged↗
PubMed1999

Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical entity characterized by a selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. Now, we report the subcellular localization of Parkin protein in patients with AR-JP or Parkinson's disease (PD) and in controls by immunoblotting and immunohistochemistry using antibodies raised against the Parkin molecule. Parkin protein was absent in all regions of the brains of patients with AR-JP. Parkin protein was not decreased in the brains of sporadic PD patients. Immunoreactivity was detected in a few Lewy bodies. Parkin protein was located in both the Golgi complex and cytosol.

Brain↗
PubMed1999

[A Parkin gene (PARK 2) and Parkinson's disease].

We identified a PARK 2 (AR-JP) family with a patient presenting with homozygous deletion of D 6 S305--a marker within the 17cM region for PARK 2 locus. Markers surrounding D 6 S305 which are mapped 0 cM apart from D 6 S305, were not deleted, indicating that PARK 2 gene is located extremely close to D 6 S305. Exon search in the inserts with average size of 100 kb of BAC clones, which harbor D 6 S305, led us to find the exonic sequences which was subsequently proved to be exon 7 of the Parkin gene. From this exon sequences, full-length cDNA was isolated, and BAC contig covering Parkin gene was generated. Homozygous deletions or frame-shift mutations in the Parkin gene were found in the patients with AR-JP/PARK 2, revealing that a loss-of-function of Parkin gene is responsible for AR-JP/PARK 2. Our findings indicate that constant production of Parkin protein is essentially required for maintaining the survival of nigral neurons. One attractive hypothesis is that Parkinson's disease and AR-JP/PARK 2 might share a common effector pathway for nigral neuronal death. In this scenario, as PARK 2 is not accompanied with Lewy body formation. Parkin might act at or downstream of synuclein aggregation, which has been recently implicated as a trigger event for neuronal death in Parkinson's disease. In any case, identification of functional targets of Parkin protein will give us an important clue to identify downstream events of neuronal death which is activated by inclusion body formation.

Cell Death↗
PubMed1998

Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. To date, we found two different deletional mutations including single and multiple exonic deletions. In the present study, we identified two types of point mutations (Thr240Arg and Gln311Stop) involving exons 6 and 8 in the parkin gene of the AR-JP patients from two Turkish families. This is the first report on point mutations for the parkin gene. Furthermore, the Thr240Arg mutation was located on a consensus sequence for the site of phosphorylation by casein kinase II. Identification of its mutation provides an important clue as to the role of the Parkin protein in degeneration of the substantia nigra in the brain of AR-JP patients.

Adolescent↗
PubMed1998

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Autosomal recessive juvenile parkinsonism (AR-JP) maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253; the former is deleted in one Japanese AR-JP patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA done of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3-7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product 'Parkin'.

Adult↗
PubMed1998

A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2).

A gene for autosomal recessive juvenile parkinsonism (ARJP; HGMW-approved symbol PARK2; MIM 600116) has recently been mapped to a 17-cM interval on chromosome 6q25.2-q27. We here report an inbred family with ARJP showing a perfect cosegregation with null allele for D6S305, which is a marker within the ARJP locus. We assigned the deletion within an interval between D6S1937 and AFMa155td9, which are 0 cM apart from each other and located on a single YAC clone. Two possibilities should be evaluated: (1) the deletion is polymorphic and linked to ARJP and (2) the deletion is pathogenic and contains both D6S305 and the ARJP gene (or a part of it). An exon search in a deleted segment or in the relatively small-sized genomic clones harboring D6S305 may enormously facilitate the cloning procedure of the ARJP gene.

Chromosome Deletion↗
PubMed1998

Association between the gene encoding the E2 subunit of the alpha-ketoglutarate dehydrogenase complex and Parkinson's disease.

Dihydrolipoamide succinyltransferase (E2, EC 2.3.1.61, chromosome 14q24.2-3) is a specific subunit of human alpha-ketoglutarate dehydrogenase complex (KGDHC). A biallelic intragenic polymorphism was identified in E2 gene of KGDHC. It was a single nucleotide substitution between G (in allele 1) and A (in allele 2) at the position that does not change amino acid code. Using this intragenic polymorphism as a marker, we investigated the association between this gene and Parkinson's disease. Frequencies of the genotypes that carry allele 2 were significantly higher in the Parkinson's disease group than in the control group. The results indicated that a genetic variant of the E2 gene itself or in close proximity to the gene constitutes one of the genetic risk factors for Parkinson's disease.

Age Distribution↗
PubMed1998

Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young-onset parkinsonism with remarkable response to levodopa. Recently, we mapped the gene locus for AR-JP to chromosome 6q25.2-q27 by linkage analysis and we identified a novel large gene, Parkin, consisting of 12 exons from this region; mutations of this gene were found to be the cause of AR-JP in two families. Now we report results of extensive molecular analysis on 34 affected individuals from 18 unrelated families with AR-JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exon 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one-base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one-base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR-JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.

Amino Acid Sequence↗
PubMed1998

Mitochondrial dysfunction in Parkinson's disease.

This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.

Cell Nucleus↗