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Biomedical subjects

Christine Klein

Publications and source records attributed to Christine Klein.

53 records · Page 3Linked to original sources
PubMed2004

Distribution, type, and origin of Parkin mutations: review and case studies.

Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.

Adult↗
PubMed2004

Family history of primary movement disorders as a predictor for neuroleptic-induced extrapyramidal symptoms.

BACKGROUND: A genetic susceptibility to extrapyramidal symptoms caused by treatment with neuroleptic medication has been suggested. AIMS: To identify predictor variables for neuroleptic-induced extrapyramidal symptoms, particularly considering family history of primary movement disorders. METHOD: We investigated 100 in-patients receiving a stable neuroleptic medication with regard to occurrence of extrapyramidal symptoms, drug history and detailed family history of primary movement disorders. RESULTS: Step-wise logistic regression analysis revealed that a positive family history was a significant predictor for lifetime prevalence of extrapyramidal symptoms, including reported and currently observed symptoms. The duration of exposure to neuroleptic medication and age were further predictors. CONCLUSIONS: Our findings underline the notion of genetic susceptibility for secondary extrapyramidal symptoms and suggest possible shared genetic factors in primary and secondary movement disorders as well as psychotic disorders.

Adolescent↗
PubMed2003

Alterations in the common fragile site gene Parkin in ovarian and other cancers.

The cloning and characterization of the common fragile site (CFS) FRA6E (6q26) identified Parkin, the gene involved in the pathogenesis of many cases of juvenile, early-onset and, rarely, late-onset Parkinson's disease, as the third large gene to be localized within a large CFS. Initial analyses of Parkin indicated that in addition to playing a role in Parkinson's disease, it might also be involved in the development and/or progression of ovarian cancer. These analyses also indicated striking similarities among the large CFS-locus genes: fragile histidine triad gene (FHIT; 3p14.2), WW domain-containing oxidoreductase gene (WWOX; 16q23), and Parkin (6q26). Analyses of FHIT and WWOX in a variety of different cancer types have identified the presence of alternative transcripts with whole exon deletions. Interestingly, various whole exon duplications and deletions have been identified for Parkin in juvenile and early-onset Parkinson's patients. Therefore, we performed mutational/exon rearrangement analysis of Parkin in ovarian cancer cell lines and primary tumors. Four (66.7%) cell lines and four (18.2%) primary tumors were identified as being heterozygous for the duplication or deletion of a Parkin exon. Additionally, three of 23 (13.0%) nonovarian tumor-derived cell lines were also identified as having a duplication or deletion of one or more Parkin exons. Analysis of Parkin protein expression with antibodies revealed that most of the ovarian cancer cell lines and primary tumors had diminished or absent Parkin expression. While functional analyses have not yet been performed for Parkin, these data suggest that like FHIT and WWOX, Parkin may represent a tumor suppressor gene.

Alternative Splicing↗
PubMed2002

Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia.

Myoclonus-dystonia (M-D) is a movement disorder characterized by rapid muscle contractions and sustained twisting and repetitive movements and has recently been associated with mutations in the epsilon-sarcoglycan gene (SGCE). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmission, suggesting a putative maternal imprinting mechanism. We present an apparently sporadic M-D case and two patients from an M-D family with seemingly autosomal recessive inheritance. In both families, we detected an SGCE mutation that was inherited from the patients' clinically unaffected fathers in an autosomal dominant fashion. Whereas, in the first family, RNA expression studies revealed expression of only the mutated allele in affected individuals and expression of the normal allele exclusively in unaffected mutation carriers, the affected individual of the second family expressed both alleles. In addition, we identified differentially methylated regions in the promoter region of the SGCE gene as a characteristic feature of imprinted genes. Using a rare polymorphism in the promoter region in a family unaffected with M-D as a marker, we demonstrated methylation of the maternal allele, in keeping with maternal imprinting of the SGCE gene. Loss of imprinting in the patient with M-D who had biallelic expression of the SGCE gene was associated with partial loss of methylation at several CpG dinucleotides.

Alleles↗
PubMed2002

The striatal dopaminergic deficit is dependent on the number of mutant alleles in a family with mutations in the parkin gene: evidence for enzymatic parkin function in humans.

Autosomal recessive parkinsonism associated with mutations in the parkin gene represents a monogenic form of hereditary parkinsonism. We performed [(18)F]6-fluorodopa (FDOPA) positron emission tomography as a measurement of the nigrostriatal dopaminergic system as well as extensive haplotype analysis of the PARK 2 gene locus in 14 subjects with parkin mutations. In parkin subjects, the reduction of striatal FDOPA uptake increased with the number of mutated alleles and was also slightly obvious in asymptomatic parkin gene carriers in the heterozygous state. The abnormal FDOPA uptake pattern in parkin patients did not significantly differ from that of sporadic Parkinson's disease. Our data are in agreement with an enzymatic dysfunction of the gene's translational product, which has been shown to promote protein degradation as an ubiquitin-protein ligase. Thus, parkinsonism in parkin gene carriers may be related to abnormal nigral protein accumulation in the presence of a suprathreshold enzyme dysfunction.

Adult↗
PubMed2002

PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study.

Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.

Adult↗
PubMed2002

Role of parkin mutations in 111 community-based patients with early-onset parkinsonism.

Early-onset parkinsonism is frequently reported in connection with mutations in the parkin gene. In this study, we present the results of extensive genetic screening for parkin mutations in 111 community-derived early-onset parkinsonism patients (age of onset <50 years) from Germany with an overall mutation rate of 9.0%. Gene dosage alterations represented 67% of the mutations found, underlining the importance of quantitative analyses of parkin. In summary, parkin mutations accounted for a low but significant percentage of early-onset parkinsonism patients in a community-derived sample.

Adult↗
PubMed2002

Epsilon-sarcoglycan mutations found in combination with other dystonia gene mutations.

Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.

Base Sequence↗
PubMed2002

[18F]-Dopa positron emission tomography imaging in early-stage, non-parkin juvenile parkinsonism.

There are few reports of positron emission tomography (PET) in juvenile parkinsonism (JP). We report on the results of (18)F-6-fluoro-L-dopa (FD) PET in a 14-year-old patient with JP of 5 years duration associated with atypical features. This is the youngest subject to be investigated to date. There was a severe asymmetric reduction in striatal FD uptake, with a rostrocaudal gradient in the putamen similar to that seen in adult-onset idiopathic parkinsonism. Extensive DNA analysis in this patient did not show mutations in the parkin gene.

Adolescent↗
PubMed2002

The pathology of the spinal cord in progressive supranuclear palsy.

We describe the results of a study of the spinal cord of 5 patients with progressive supranuclear palsy (PSP). Examination of the 6th cervical, 7th thoracic, and 5th lumbar segments revealed variable degree of gliosis and density of neuropil threads (NTs), nerve cell loss, and tau-positive cytoplasmic staining of neurons, some of which was reminiscent of neurofibrillary tangles (NFT). Tau-positive neurons were seen at each spinal level and in the 3 zones in which each level was subdivided. Cells with the appearance of NFT predominated in the intermediate zone. Morphometric study revealed 47%, 52%, and 32% decrease in cell numbers in the motor area (lamina IX) at the 3 spinal levels, respectively, and 39% in the intermedio-lateral column. This is the first report describing severe neuronal loss throughout the whole spinal cord in patients with PSP and its results are in keeping with a previous study of the nucleus of Onufrowicz. The reasons why cell loss fails to produce clinical symptoms are analyzed and the clinico-pathological correlations between anatomical changes and dystonia are considered. On the basis of existing data, we conclude that previous suggestions implicating spinal interneurons in the pathogenesis of neck dystonia should not be supported.

Aged↗
PubMed2002

Dystonia: clinical features, genetics, and treatment.

PURPOSE OF REVIEW: The present review covers recent advances in dystonia research related to dystonia genetics and treatment. These have led to the discovery of novel dystonia genes and loci, to changing classification schemes, and to the introduction of improved and new treatment options. RECENT FINDINGS: Currently 13 different forms of dystonia can be distinguished on a genetic basis (dystonia types 1-13). Recently, a novel gene locus (DYT13) was detected in a family with segmental dystonia, and the gene causing myoclonus-dystonia was identified (SGCE). Furthermore, a novel mutation in the DYT1 gene is associated with a myoclonus-dystonia phenotype. Regarding dystonia treatment, patients refractory to botulinum toxin type A can now be treated with botulinum toxin type B. Selective peripheral denervation remains an effective form of treatment for patients with secondary, but probably not with primary botulinum toxin treatment failure. Finally, a renaissance of functional surgical ablative procedures has taken place, with high frequency deep brain stimulation being introduced in dystonia treatment. Bilateral pallidotomy or pallidal stimulation may provide major benefit especially in patients with generalized, disabling dystonia with the most dramatic improvements in dystonia type 1 patients. Neurostimulation may also be effective in primary segmental axial dystonia, myoclonus-dystonia, and tardive dystonia. SUMMARY: The recent mapping of additional dystonia gene loci, the identification of novel dystonia genes, and the characterization of proteins encoded by these genes have enhanced our understanding of various forms and aspects of the dystonias and have opened up new avenues for research. Treatment options include both medical and surgical therapies, with deep brain simulation being the most recent development.

Carrier Proteins↗