Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa.

Parkinson's disease is a frequent disorder caused primarily by the loss of dopaminergic neurons of the substantia nigra. Mutations in the PTEN-induced kinase (PINK1) gene, in addition to those in parkin and DJ-1, have been found in families with recessive early-onset Parkinson's disease. We screened for parkin and PINK1 mutations in a panel of 177 autosomal recessive Parkinson's disease families with ages at onset < or =60 years, mostly from Europe. In 7 unrelated families, we identified 10 pathogenic PINK1 mutations (5 missense, 2 nonsense and 3 frameshift deletion mutations), 8 of which were novel. All the mutations were in the homozygous or compound heterozygous states. Interestingly, pseudo-dominant inheritance was observed in a family with two different mutations. The clinical characteristics of 12 PINK1 patients and 114 parkin patients were similar, even for signs such as dystonia at onset and increased reflexes, which were thought to be specific to parkin. In contrast, onset in patients with PINK1 mutations was earlier and increased reflexes were found more frequently than in patients without PINK1 or parkin mutations. These results suggest that PINK1 is the second most frequent causative gene in early-onset Parkinson's disease with a slowly progressive phenotype, indistinguishable from early-onset patients with parkin mutations.

[1]  Christine Klein,et al.  Early-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes , 2005 .

[2]  P. Bauer,et al.  PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism , 2005, European Journal of Human Genetics.

[3]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[4]  David W. Miller,et al.  Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[6]  Pietro Cortelli,et al.  Homozygous PINK1 C‐terminus mutation causing early‐onset parkinsonism , 2004, Annals of neurology.

[7]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[8]  M. Farrer,et al.  Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects. , 2001, American journal of human genetics.

[9]  K. Kessler,et al.  Dopaminergic function in a family with the PARK6 form of autosomal recessive Parkinson’s syndrome , 2005, Journal of Neural Transmission.

[10]  A. Bentivoglio,et al.  PINK1 mutations are associated with sporadic early‐onset parkinsonism , 2004, Annals of neurology.

[11]  J. Hoenicka,et al.  Molecular findings in familial Parkinson disease in Spain. , 2002, Archives of neurology.

[12]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[13]  Alexandra Durr,et al.  How much phenotypic variation can be attributed to parkin genotype? , 2003, Annals of neurology.

[14]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[15]  J. Haines,et al.  Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease , 2003, Annals of neurology.

[16]  Bonifati,et al.  Association between early-onset Parkinson's disease and mutations in the parkin gene. , 2000, The New England journal of medicine.

[17]  Jean-François Deleuze,et al.  Complex relationship between Parkin mutations and Parkinson disease. , 2002, American journal of medical genetics.

[18]  Georg Auburger,et al.  The ubiquitin pathway in Parkinson's disease , 1998, Nature.

[19]  Y. Agid,et al.  Screening for DJ-1 mutations in early onset autosomal recessive parkinsonism , 2003, Neurology.

[20]  A. Albanese,et al.  The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease , 2005, Neurology.

[21]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[22]  J. Winn,et al.  Brain , 1878, The Lancet.

[23]  Vincenzo Bonifati,et al.  Early‐onset Parkinson's disease caused by a compound heterozygous DJ‐1 mutation , 2003, Annals of neurology.

[24]  K. Marder,et al.  Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations , 2002, Neurology.

[25]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[26]  N. Wood,et al.  PINK1 (PARK6) associated Parkinson disease in Ireland , 2004, Neurology.

[27]  C. Klein,et al.  Early-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes , 2005, Neurology.

[28]  Janel O. Johnson,et al.  Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. , 2004, Archives of neurology.

[29]  N. Quinn,et al.  The role of pathogenic DJ‐1 mutations in Parkinson's disease , 2003, Annals of neurology.

[30]  N. Hattori,et al.  Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism , 2005, Neurology.

[31]  Nobutaka Hattori,et al.  Novel PINK1 mutations in early‐onset parkinsonism , 2004, Annals of neurology.

[32]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[33]  Paola Piccini,et al.  Clinical and subclinical dopaminergic dysfunction in PARK6‐linked parkinsonism: An 18F‐dopa PET study , 2002, Annals of neurology.

[34]  Y. Agid,et al.  Parkin mutations are frequent in patients with isolated early-onset parkinsonism. , 2003, Brain : a journal of neurology.

[35]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.