Studies Link Gene Mutation to Parkinson's Disease
Lancet 2005: 365(9455), 15 January 2005
Three teams of scientists have identified a genetic mutation that is linked to about 5 percent of inherited cases of Parkinson's disease.
The fault on the recently discovered LRRK2 gene is one of five genetic defects linked to the progressive nervous system disorder and could lead to improved diagnosis and the development of a genetic test.
"Our results suggest that the mutation we have studied is the most common cause of Parkinson's disease identified to date," said Dr Tatiana Foroud, an associate professor at Indiana University School of Medicine in Indianapolis.
"We found there is a novel mutation which is common in these families," Bonifati said in an interview. "The other groups in the UK and the US found the same mutation independently."
"The main challenge is now to try and understand how this and other Parkinson disease-associated LRRK2 mutations lead to neurodegenerative disease, in order to design novel therapeutic and preventive strategies," he added. (Reuters)
Summary
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause some forms of autosomal dominant Parkinson's disease. We measured the frequency of a novel mutation (Gly2019Ser) in familial Parkinson's disease by screening genomic DNA of patients and controls. Of 767 affected individuals from 358 multiplex families, 35 (5%) individuals were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic Parkinson's disease. Thus, our results suggest that a single LRRK2 mutation causes Parkinson's disease in 5% of individuals with familial disease. Screening for this mutation should be a component of genetic testing for Parkinson's disease.
posted by Permphan @ 4:23 PM
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3 Comments:
This is another related paper.
Neuron. 2004 Nov 18;44(4):601-7.(PMID: 15541309)
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
From Department of Neurodegenerative Disease, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany.
ABSTRACT:
We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
This is another paper pubished in the same volume of Neuron, but from a different institute.
Neuron. 2004 Nov 18;44(4):595-600.(PMID: 15541308)
"Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease."
Unitat de Genetica Molecular, Departament de Genomica i Proteomica, Institut de Biomedicina de Valencia-CSIC, Spain.
ABSTRACT:
Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein "dardarin", derived from the Basque word dardara, meaning tremor.
Here is what Funayama and colleague have found:
Funayama et al. (2002) performed a genomewide linkage analysis in the family reported by Hasegawa and Kowa (1997). Allele typing was performed for 31 individuals from 4 generations. Parametric 2-point linkage analysis yielded a highest lod score of 4.32 at D12S345 (12p11.2). Parametric multipoint linkage analysis of the 13.6-cM interval around this marker yielded lod scores greater than 4.0 at D12S85 (12q12). Haplotype analysis showed 2 recombination events which further defined the candidate region. The haplotype was shared by 15 affected individuals and by 8 unaffected individuals, which raised the possibility of incomplete penetrance. Nonparametric linkage analysis also supported mapping of the parkinsonism locus to 12p11.2-q13.1.
In 21 Caucasian families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission, Zimprich et al. (2004) tested for linkage to the PARK8 region. Two families, one a German Canadian family and the other a family from western Nebraska, reached significant linkage on their own, with a combined maximum multipoint lod score of 3.33.
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