Share This Article:

Parkin and LRRK2/Dardarin Mutations in Early Onset Parkinson’s Disease in the Basque Country (Spain)

Abstract Full-Text HTML XML Download Download as PDF (Size:450KB) PP. 101-108
DOI: 10.4236/jbbs.2015.53010    2,662 Downloads   3,038 Views  

ABSTRACT

We have performed a complete screening of the Parkin gene (PRKN2) and looked for p.Gly2019Ser (G2019S) and p.Arg1441Gly (R1441G) LRRK2/dardarin gene mutations in twenty seven patients with Parkinson’s disease (PD) with an age at onset younger than 50 years (EOPD), living in Gipuzkoa (Basque Country, Spain). Thirteen of them (48%) were PRKN2 mutation carriers. The c.255-256DelA mutation was the most frequent, followed by a deletion involving exons 3 and 4. A deletion involving exons 3 and 12 of the PRKN2 gene and R1441G LRRK2 mutation was found together in one PD patient. Four out of fourteen PRKN2 negative patients carried the p.G2019S mutation. Both PRKN2 mutation carriers and non-carriers presented frequently with family history (10 PRKN2 mutation carriers and 8 PRKN2 non-carriers); in fact, five patients without a known gene mutation had a first degree relative affected, suggesting another monogenic disease. PRKN2 carriers presented with a younger age at onset (36.7 vs. 41.7) and more benign disease progression. Indeed, those PD patients younger than forty who initially presented with unilateral tremor became shortly bilateral. Relatively, symmetric parkinsonism and slow disease progression carried more frequently PRKN2 mutations than patients with unilateral akinetic rigid parkinsonism and age at onset later than 40 years. As expected in a recessive disease, PRKN2 patients present more often with affected siblings and unaffected patients. The G2019S LRRK2 mutation, less prevalent than R1441G in our area, may be also a frequent cause of PD in EOPD (4 patients).

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Massó, J. , Ruiz-Martínez, J. , Paisán-Ruiz, C. , Gorostidi, A. , Bergareche, A. , de Munain, A. , Alzualde, A. and Pérez-Tur, J. (2015) Parkin and LRRK2/Dardarin Mutations in Early Onset Parkinson’s Disease in the Basque Country (Spain). Journal of Behavioral and Brain Science, 5, 101-108. doi: 10.4236/jbbs.2015.53010.

References

[1] Kitada, T., Asakawa, S., et al. (1998) Mutations in the Parkin Gene Cause Autosomal Recessive Juvenile Parkinsonism. Nature, 392, 605-608.
http://dx.doi.org/10.1038/33416
[2] Bonifati, V., Rizzu, P., van Baren, M.J., et al. (2003) Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism. Science, 299, 256-259.
http://dx.doi.org/10.1126/science.1077209
[3] Valente, E.M, Abou-Sleiman, P.M., et al. (2004) Hereditary Early-Onset Parkinson’s Disease Caused by Mutations in PINK1. Science, 304, 1158-1160.
http://dx.doi.org/10.1126/science.1096284
[4] Shimura, H., Hattori, N., et al. (2000) Familial Parkinson Disease Gene Product, Parkin, Is a Ubiquitin-Protein Ligase. Nature Genetics, 25, 302-305.
http://dx.doi.org/10.1038/77060
[5] Zhang, Y., Gao, J., et al. (2000) Parkin Functions as an E2-Dependent Ubiquitin-Protein Ligase and Promotes the Degradation of the Synaptic Vesicle-Associated Protein, CDCrel-1. Proceedings of the National Academy of Sciences of the United States of America, 97, 13354-13359.
http://dx.doi.org/10.1073/pnas.240347797
[6] Lücking, C.B., Durr, A., et al. (2000) Association between Early-Onset Parkinson’s Disease and Mutations in the Parkin Gene. French Parkinson’s Disease Genetics Study Group. The New England Journal of Medicine, 342, 1560-1567.
http://dx.doi.org/10.1056/NEJM200005253422103
[7] Nichols, W.C., Pankratz, N., Uniacke, S.K., et al. (2002) Linkage Stratification and Mutation Analysis at the Parkin Locus Identifies Mutation Positive Parkinson’s Disease Families. Journal of Medical Genetics, 39, 489-492.
http://dx.doi.org/10.1136/jmg.39.7.489
[8] Farrer, M., Chan, P., Chen, R., Tan, L., Lincoln, S., Hernandez, D., et al. (2001) Lewy Bodies and Parkinsonism in Families with Parkin Mutations. Annals of Neurology, 50, 293-300.
http://dx.doi.org/10.1002/ana.1132
[9] Pramstaller, P.P., Schlossmacher, M.G., Jacques, T.S., Scaravilli, F., Eskelson, C., Pepivani, I., Hedrich, K., Adel, S., Gonzales-McNeal, M., Hilker, R., Kramer, P.L. and Klein, C. (2005) Lewy Body Parkinson’s Disease in a Large Pedigree with 77 Parkin Mutation Carriers. Annals of Neurology, 58, 411-422.
http://dx.doi.org/10.1002/ana.20587
[10] Paisan-Ruiz, C., Jain, S., Evans, E.W., Gilks, W.P., Simon, J., van der Brug, M., Lopez de Munain, A., Aparicio, S., Gil, A.M., Khan, N., Johnson, J., Martinez, J.R., Nicholl, D., Carrera, I.M., Pena, A.S., de Silva, R., Lees, A., Marti-Masso, J.F., Perez-Tur, J., Wood, N.W. and Singleton, A.B. (2004) Cloning of the Gene Containing Mutations That Cause PARK8-Linked Parkinson’ Disease. Neuron, 44, 595-600.
http://dx.doi.org/10.1016/j.neuron.2004.10.023
[11] Gorostidi, A., Ruiz-Martínez, J., Lopez de Munain, A., Alzualde, A. and Martí Massó, J.F. (2009) LRRK2 G2019S and R1441G Mutations Associated with Parkinson’s Disease Are Common in the Basque Country, but Relative Prevalence Is Determined by Ethnicity. Neurogenetics, 10, 157-159.
http://dx.doi.org/10.1007/s10048-008-0162-0
[12] Gelb, D.J., Oliver, E. and Gilman, S. (1999) Diagnostic Criteria for Parkinson Disease. Archives of Neurology, 56, 33-39.
http://dx.doi.org/10.1001/archneur.56.1.33
[13] Hoehn, M.M. and Yahr, M.D. (1967) Parkinsonism: Onset, Progression and Mortality. Neurology, 17, 427-442.
http://dx.doi.org/10.1212/WNL.17.5.427
[14] Fahn, S. and Elton, R. (1987) Members of the updrs Development Committee. In: Fahn, S., Marsden, C.D., Calne, D.B. and Goldstein, M., Eds., Recent Developments in Parkinson’s Disease, Vol. 2, Macmillan Health Care Information, Florham Park, 153-163, 293-304.
[15] Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. and Sekiya, T. (1989) Detection of Polymorphisms of Human DNA by Gel Electrophoresis as Single-Strand Conformation Polymorphisms. Proceedings of the National Academy of Sciences of USA, 86, 2766-2770.
http://dx.doi.org/10.1073/pnas.86.8.2766
[16] Lucking, C.B. and Brice, A. (2003) Semiquantitative PCR for the Detection of Exon Rearrangements in the Parkin Gene. Methods in Molecular Biology, 217, 13-26.
[17] Bergareche, A., De La Puente, E., Lopez de Munain, A., Sarasqueta, C., Poza, J.J. and Marti-Masso, J.F. (2004) Prevalence of Parkinson’s Disease and Other Types of Parkinsonism. A Door-to-Door Survey in Bidasoa, Spain. Journal of Neurology, 251, 340-345.
http://dx.doi.org/10.1007/s00415-004-0333-3
[18] Hedrich, K., Eskelson, C., Wilmot, B., Marder, K., Harris, J., Garrels, J., et al. (2004) Distribution, Type, and Origin of Parkin Mutations: Review and Case Studies. Movement Disorders, 10, 1146-1157.
http://dx.doi.org/10.1002/mds.20234
[19] Munoz, E., Tolosa, E., Pastor, P., Marti, M.J., Valldeoriola, F., Campdelacreu, J. and Oliva, R. (2002) Relative High Frequency of the c.255delA Parkin Gene Mutation in Spanish Patients with Autosomal Recessive Parkinsonism. Journal of Neurology, Neurosurgery, and Psychiatry, 5, 582-584.
[20] Hedrich, K., Kann, M., Lanthaler, A.J., Dalski, A., Eskelson, C., Landt, O., et al. (2001) The Importance of Gene Dosage Studies: Mutational Analysis of the Parkin Gene in Early-Onset Parkinsonism. Human Molecular Genetics, 10, 1649-1656.
http://dx.doi.org/10.1093/hmg/10.16.1649
[21] Khan, N.L., Graham, E., Critchley, P., Schrag, A.E., Wood, N.W., Lees, A.J., et al. (2003) Parkin Disease: A Phenotypic Study of a Large Case Series. Brain, 126, 1279-1292.
http://dx.doi.org/10.1093/brain/awg142
[22] Periquet, M., Latouche, M., Lohmann, E., Rawal, N., De Michele, G., Ricard, S., et al. (2003) Parkin Mutations Are Frequent in Patients with Isolated Early-Onset Parkinsonism. Brain, 126, 1271-1278.
http://dx.doi.org/10.1093/brain/awg136
[23] Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jiménez-Jiménez, J., Berciano, J., et al. (2002) Molecular Findings in Familial Parkinson Disease in Spain. Archives of Neurology, 59, 966-970.
http://dx.doi.org/10.1001/archneur.59.6.966

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.