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From the Department of Clinical Genetics (Drs. Bonifati, Maat-Kievit, de Klein, and Oostra, and C.F. Rohé and G.J. Breedveld), Erasmus MC Rotterdam, The Netherlands; Department of Neurological Sciences "La Sapienza" University (Drs. Bonifati, Fabrizio, Fabbrini, and Meco), Rome, Italy; Department of Neurology (Drs. De Mari, Lamberti), University of Bari, Italy; Institute IRCCS "Mondino" (Drs. Tassorelli, Martignoni), Pavia, Italy; Department of Neuroscience (Drs. Tavella, Lopiano), University of Turin, Italy; Neurology Division (Dr. Marconi), "Misericordia" Hospital, Grosseto, Italy; Department of Neurology (Dr. Nicholl), Queen Elizabeth Hospital, Birmingham, UK; Department of Neurology (Drs. Chien and Barbosa), University of São Paulo, Brazil; Department of Neurology (Dr. Fincati), University of Verona, Italy; Department of Neurosciences, Ophthalmology & Genetics (Dr. Abbruzzese), University of Genova, Italy; Department of Neurology (Dr. Marini), University of Florence, Italy; Neurology Division (Dr. De Gaetano), Hospital of Castrovillari, Italy; Department of Neurology (Dr. Horstink), Nijmegen Academic Hospital, The Netherlands; Neurological Clinical Research Unit (Dr. Sampaio), Institute of Molecular Medicine, Lisbon, Portugal; Parkinson Institute (Drs. Antonini and Goldwurm), Istituti Clinici di Perfezionamento, Milan, Italy; IRCCS Neuromed (Dr. Stocchi), Pozzilli, Italy; Department of Neurology (Dr. Montagna), University of Bologna, Italy; Neurology Division (Dr. Toni), Hospital of Casarano, Italy; Neurology Division (Dr. Guidi), INRCA Institute, Ancona, Italy; Neurology Division (Dr. Dalla Libera), "Boldrini" Hospital, Thiene, Italy; Neurology Division (Dr. Tinazzi), "Borgo Trento" Hospital, Verona, Italy; Neurology Division (Dr. De Pandis), Hospital "Villa Margherita," Benevento, Italy; A. Avogadro University (Dr. Martignoni), Novara, Italy; and National Centre of Epidemiology (Dr. Vanacore), National Institute for Health, Rome, Italy.
Address correspondence and reprint requests to Dr. V. Bonifati, Dept. Clinical Genetics, Erasmus MC Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands; e-mail: v.bonifati{at}erasmusmc.nl
Objective: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism.
Methods: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.
Results: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.
Conclusions: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 12 issue to find the title link for this article.
*Members of The Italian Parkinson Genetics Network are listed in the Appendix.
Supported by the National Parkinson Foundation (USA); the Stichting Klinische Genetica Rotterdam (The Netherlands); the Ministero dell’Istruzione, Universita’ e Ricerca (MIUR, Italy); and the IRCCS "Mondino" (Italy). The DNA samples contributed by the Parkinson Institute-Istituti Clinici di Perfezionamento, Milan, Italy, were from the "Human genetic bank of patients affected by PD and parkinsonisms," supported by Telethon grant n. GTF03009.
Received December 12, 2004. Accepted in final form March 29, 2005.
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