Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

Abstract

Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.

Keywords: :

• CALHM genes
• Creutzfeldt-Jakob disease
• calcium homeostasis
• genetic risk
• linkage disequilibrium

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank to all physicians and the epidemiological and clinical coordinators for assistance and notifying cases to the CJD Spanish Registry, as well as to F. Avellanal, J. Almazán, M. Ruiz, and E. Alcalde for their collaboration with the Spanish CJD surveillance system. We are thankful to the Biobank from the Hospital Universitario Fundación Alcorcón for providing neuropathological data to the CJD Spanish Registry of an important number of sCJD cases. This work was made possible by the generous participation of patients, control subjects and their families.

Author Contributions

Conceived and designed the experiments: OC MJB MC. Performed the experiments: OC MJB RH IS. Analyzed the data: OC MC. Contributed materials: MJB JC AFG PMM AL MJR AR JdP IF MC. Wrote the manuscript: OC JdP MC. Critical revision of the manuscript: MJB JC AL IF.

Funding

This work was supported by grants FIS 05/0912 from the Ministerio de Ciencia e Innovación, DGSP from Ministerio de Sanidad, Política Social e Igualdad (MC), the DGSP of the Spanish National Health Ministry (MC), and the Spanish CIBERNED (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas) network (MJB, AL, JdP, IF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Note

Supplemental material can be found at: http://www.landesbioscience.com/journals/prion/article/20785/