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The p. R151C Polymorphism in MC1R Gene Modifies the Age of Onset in Spanish Huntington’s Disease Patients

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Abstract

The expansion of CAG repeats (≥36 CAG) in the HTT gene is the only known genetic cause of Huntington’s disease (HD) and the main determinant of the course of the disease. The length of the expanded CAG repeats correlates inversely with the age of onset (AOO) but does not completely determine it. We investigated the role of the melanocortin 1 receptor (MC1R) gene as a modifier factor of AOO in 600 HD patients from Spain. We sequenced the entire region of the MC1R gene and analyzed all the nonsynonymous MC1R genetic variants with a minor allele frequency of at least 0.01 in HD patients. The variability in AOO attributable to the CAG repeats and MC1R polymorphisms was evaluated using a multiple linear regression model. We found that the loss-of-function p. R151C MC1R polymorphism has a significant influence on the AOO (P = 0.004; Bonferroni-corrected P = 0.032) which explains 1.42% of the variance in AOO that cannot be accounted for by the expanded CAG repeat. Our results suggest that the MC1R gene could modify the AOO in Spanish HD patients and encourage the evaluation of loss-of-function MC1R polymorphisms in other HD populations with a higher frequency of these MC1R polymorphisms.

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References

  1. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group (1993). Cell 72 (6):971–983

  2. Arning L, Monte D, Hansen W, Wieczorek S, Jagiello P, Akkad DA, Andrich J, Kraus PH et al (2008) ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. J Mol Med (Berl) 86(4):485–490. doi:10.1007/s00109-007-0299-6

    Article  CAS  Google Scholar 

  3. Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S, Arning L (2009) PGC-1alpha as modifier of onset age in Huntington disease. Mol Neurodegener 4:10. doi:10.1186/1750-1326-4-10

    Article  PubMed  PubMed Central  Google Scholar 

  4. Metzger S, Rong J, Nguyen HP, Cape A, Tomiuk J, Soehn AS, Propping P, Freudenberg-Hua Y et al (2008) Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease. Hum Mol Genet 17(8):1137–1146. doi:10.1093/hmg/ddn003

    Article  CAS  PubMed  Google Scholar 

  5. Dhaenens CM, Burnouf S, Simonin C, Van Brussel E, Duhamel A, Defebvre L, Duru C, Vuillaume I et al (2009) A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease. Neurobiol Dis 35(3):474–476. doi:10.1016/j.nbd.2009.06.009

    Article  CAS  PubMed  Google Scholar 

  6. Arning L, Saft C, Wieczorek S, Andrich J, Kraus PH, Epplen JT (2007) NR2A and NR2B receptor gene variations modify age at onset in Huntington disease in a sex-specific manner. Hum Genet 122(2):175–182. doi:10.1007/s00439-007-0393-4

    Article  CAS  PubMed  Google Scholar 

  7. Metzger S, Saukko M, Van Che H, Tong L, Puder Y, Riess O, Nguyen HP (2010) Age at onset in Huntington's disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum Genet 128(4):453–459. doi:10.1007/s00439-010-0873-9

    Article  CAS  PubMed  Google Scholar 

  8. Metzger S, Bauer P, Tomiuk J, Laccone F, Didonato S, Gellera C, Soliveri P, Lange HW et al (2006) The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease. Neurogenetics 7(1):27–30. doi:10.1007/s10048-005-0023-z

    Article  CAS  PubMed  Google Scholar 

  9. Pinto RM, Dragileva E, Kirby A, Lloret A, Lopez E, St Claire J, Panigrahi GB, Hou C et al (2013) Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches. PLoS Genet 9(10):e1003930. doi:10.1371/journal.pgen.1003930

    Article  PubMed  PubMed Central  Google Scholar 

  10. Abdel-Malek ZA, Swope VB, Starner RJ, Koikov L, Cassidy P, Leachman S (2014) Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention. Arch Biochem Biophys. doi:10.1016/j.abb.2014.07.002

    PubMed  Google Scholar 

  11. Catania A (2008) Neuroprotective actions of melanocortins: a therapeutic opportunity. Trends Neurosci 31(7):353–360. doi:10.1016/j.tins.2008.04.002

    Article  CAS  PubMed  Google Scholar 

  12. Puig-Butille JA, Escamez MJ, Garcia-Garcia F, Tell-Marti G, Fabra A, Martinez-Santamaria L, Badenas C, Aguilera P et al (2014) Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer. Oncotarget 5(6):1439–1451

    Article  PubMed  Google Scholar 

  13. Mitra D, Luo X, Morgan A, Wang J, Hoang MP, Lo J, Guerrero CR, Lennerz JK et al (2012) An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491(7424):449–453. doi:10.1038/nature11624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington's disease. Brain Pathol 9(1):147–163

    Article  CAS  PubMed  Google Scholar 

  15. Warner JP, Barron LH, Brock DJ (1993) A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. Mol Cell Probes 7(3):235–239. doi:10.1006/mcpr.1993.1034

    Article  CAS  PubMed  Google Scholar 

  16. Tell-Marti G, Puig-Butille JA, Potrony M, Badenas C, Mila M, Malvehy J, Marti MJ, Ezquerra M et al (2015) The MC1R melanoma risk variant p.R160W is associated with Parkinson disease. Ann Neurol. doi:10.1002/ana.24373

    Google Scholar 

  17. Ramos-Arroyo MA, Moreno S, Valiente A (2005) Incidence and mutation rates of Huntington's disease in Spain: experience of 9 years of direct genetic testing. J Neurol Neurosurg Psychiatry 76(3):337–342. doi:10.1136/jnnp.2004.036806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Scherer D, Nagore E, Bermejo JL, Figl A, Botella-Estrada R, Thirumaran RK, Angelini S, Hemminki K et al (2009) Melanocortin receptor 1 variants and melanoma risk: a study of 2 European populations. Int J Cancer 125(8):1868–1875. doi:10.1002/ijc.24548

    Article  CAS  PubMed  Google Scholar 

  19. Cordoba-Lanus E, Hernandez-Jimenez JG, Medina-Coello C, Espinoza-Jimenez A, Gonzalez A, Rodriguez-Perez MD, Carretero-Hernandez G, Almeida P et al (2014) MC1R gene variants and sporadic malignant melanoma susceptibility in the Canary Islands population. Arch Dermatol Res 306(1):51–58. doi:10.1007/s00403-013-1420-z

    Article  CAS  PubMed  Google Scholar 

  20. Gao X, Simon KC, Han J, Schwarzschild MA, Ascherio A (2009) Genetic determinants of hair color and Parkinson's disease risk. Ann Neurol 65(1):76–82. doi:10.1002/ana.21535

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dessinioti C, Antoniou C, Katsambas A, Stratigos AJ (2011) Melanocortin 1 receptor variants: functional role and pigmentary associations. Photochem Photobiol 87(5):978–987. doi:10.1111/j.1751-1097.2011.00970.x

    Article  CAS  PubMed  Google Scholar 

  22. Garcia-Borron JC, Abdel-Malek Z, Jimenez-Cervantes C (2014) MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation. Pigment Cell Melanoma Res 27(5):699–720. doi:10.1111/pcmr.12257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to the patients for participating in the study, to the geneticists for providing DNA samples, and to Pablo Gonzalez Navarro, technician from the Department of Genetics-Jimenez Diaz Foundation University Hospital (IIS-FJD), for his work in relation to this project.

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Authors and Affiliations

  1. Dermatology Department, Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain

    Gemma Tell-Marti, Pol Gimenez-Xavier, Ariadna Segu-Roig, Miriam Potrony & Susana Puig

  2. Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain

    Gemma Tell-Marti, Joan Anton Puig-Butille, Pol Gimenez-Xavier, Celia Badenas, José M. Millán, María José Trujillo-Tiebas, Montserrat Milà & Susana Puig

  3. Biochemical and Molecular Genetics Service, Hospital Clinic & IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain

    Joan Anton Puig-Butille, Celia Badenas & Montserrat Milà

  4. Laboratorio de Genética. AGC Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain

    Victoria Alvarez

  5. Instituto de Investigación Sanitaria Hospital La Fe, IIS-La Fe, Valencia, Spain

    José M. Millán

  6. Department of Genetics, Health Research Institute–Jimenez Diaz Foundation University Hospital (IIS-FJD), Madrid, Spain

    María José Trujillo-Tiebas

  7. Medical Genetics Department, Complejo Hospitalario de Navarra, IdiSNA, Navarra Institute for Health Research, Irunlarrea 4, 31008, Pamplona, Navarra, Spain

    María A Ramos-Arroyo

  8. Medicine Department, Universitat de Barcelona, Barcelona, Spain

    Susana Puig

Authors
  1. Gemma Tell-Marti
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  2. Joan Anton Puig-Butille
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  3. Pol Gimenez-Xavier
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  4. Ariadna Segu-Roig
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  5. Miriam Potrony
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  6. Celia Badenas
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  7. Victoria Alvarez
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  8. José M. Millán
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  9. María José Trujillo-Tiebas
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  10. María A Ramos-Arroyo
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  11. Montserrat Milà
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  12. Susana Puig
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Corresponding author

Correspondence to Susana Puig.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

The research at the Melanoma Unit in Barcelona is partially funded by the Grants from Fondo de Investigaciones Sanitarias (12/00840) Spain, by the AGAUR 2014_SGR_603 of the Catalan Government, Spain, by the European Commission under the 6th Framework Programme, Contract nr: LSHC-CT-2006-018702 (GenoMEL), and by the National Cancer Institute (NCI) of the US National Institute of Health (NIH) (CA83115). Miriam Potrony is the recipient of a PhD Fellowship FI14/00231 (PFIS) from Instituto de Salud Carlos III, Spain.

Additional information

Montserrat Milà and Susana Puig contributed equally to this work.

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Tell-Marti, G., Puig-Butille, J.A., Gimenez-Xavier, P. et al. The p. R151C Polymorphism in MC1R Gene Modifies the Age of Onset in Spanish Huntington’s Disease Patients. Mol Neurobiol 54, 3906–3910 (2017). https://doi.org/10.1007/s12035-016-0305-5

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  • DOI: https://doi.org/10.1007/s12035-016-0305-5

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