neurogenetics

, Volume 14, Issue 1, pp 11–22 | Cite as

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

  • Sandy Chan Hsu
  • Renee L. Sears
  • Roberta R. Lemos
  • Beatriz Quintáns
  • Alden Huang
  • Elizabeth Spiteri
  • Lisette Nevarez
  • Catherine Mamah
  • Mayana Zatz
  • Kerrie D. Pierce
  • Janice M. Fullerton
  • John C. Adair
  • Jon E. Berner
  • Matthew Bower
  • Henry Brodaty
  • Olga Carmona
  • Valerija Dobricić
  • Brent L. Fogel
  • Daniel García-Estevez
  • Jill Goldman
  • John L. Goudreau
  • Suellen Hopfer
  • Milena Janković
  • Serge Jaumà
  • Joanna C. Jen
  • Suppachok Kirdlarp
  • Joerg Klepper
  • Vladimir Kostić
  • Anthony E. Lang
  • Agnès Linglart
  • Melissa K. Maisenbacher
  • Bala V. Manyam
  • Pietro Mazzoni
  • Zofia Miedzybrodzka
  • Witoon Mitarnun
  • Philip B. Mitchell
  • Jennifer Mueller
  • Ivana Novaković
  • Martin Paucar
  • Henry Paulson
  • Sheila A. Simpson
  • Per Svenningsson
  • Paul Tuite
  • Jerrold Vitek
  • Suppachok Wetchaphanphesat
  • Charles Williams
  • Michele Yang
  • Peter R. Schofield
  • João R. M. de Oliveira
  • María-Jesús Sobrido
  • Daniel H. Geschwind
  • Giovanni Coppola
Original Article

Abstract

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

Keywords

Basal ganglia calcification Fahr's Genetics Sequencing Mutations 

Notes

Acknowledgments

We would like to acknowledge and thank all of the participants and families for their valuable contribution to our study. This work was funded by NIH/NINDS (R01 NS040752 to DHG), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico to JRMO and MZ), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior to JRMO), FAPESP/CEPID (State of São Paulo Research Foundation to MZ), FACEPE (Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco to JRMO), Australian NHMRC (program grant 510135 to PBM), Ministry of Education and Science, Republic of Serbia (grant no. 175090 to VK, MJ, VD, and IN), and NIMH (K08 MH86297 to BLF). MJS and BQ are supported by research contracts from the Institute of Health Carlos III, European Regional Development Funds (FEDER) and the Botin Foundation. JG is supported by NIH (PSO AG008702-22 to M. Shelanski).

Conflict of interest

AEL declares that he has served as an advisor for Abbott, Allon Therapeutics, Astra Zenica, Avanir Pharmaceuticals, Biovail, Boerhinger-Ingelheim, BMS Cephalon, Ceregene, Eisai, GSK, Lundbeck A/S, Medtronic, Merck Serono, MSD, Novartis, Santhera, Solvay, and Teva; received grants from Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, Parkinson Society of Canada, and Ontario Problem Gambling Research Centre; received publishing royalties from Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press; and has served as an expert witness in cases related to the welding industry. All the other authors have no conflicts to disclose.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Sandy Chan Hsu
    • 1
  • Renee L. Sears
    • 1
  • Roberta R. Lemos
    • 2
    • 3
  • Beatriz Quintáns
    • 2
    • 4
  • Alden Huang
    • 1
  • Elizabeth Spiteri
    • 1
    • 5
  • Lisette Nevarez
    • 1
  • Catherine Mamah
    • 1
    • 6
  • Mayana Zatz
    • 7
  • Kerrie D. Pierce
    • 8
  • Janice M. Fullerton
    • 8
    • 9
  • John C. Adair
    • 10
  • Jon E. Berner
    • 11
  • Matthew Bower
    • 12
  • Henry Brodaty
    • 13
  • Olga Carmona
    • 14
  • Valerija Dobricić
    • 15
  • Brent L. Fogel
    • 1
  • Daniel García-Estevez
    • 16
  • Jill Goldman
    • 17
  • John L. Goudreau
    • 18
  • Suellen Hopfer
    • 1
    • 19
  • Milena Janković
    • 15
  • Serge Jaumà
    • 20
  • Joanna C. Jen
    • 1
  • Suppachok Kirdlarp
    • 21
  • Joerg Klepper
    • 22
  • Vladimir Kostić
    • 15
  • Anthony E. Lang
    • 23
  • Agnès Linglart
    • 24
  • Melissa K. Maisenbacher
    • 25
  • Bala V. Manyam
    • 26
  • Pietro Mazzoni
    • 17
  • Zofia Miedzybrodzka
    • 27
  • Witoon Mitarnun
    • 21
  • Philip B. Mitchell
    • 28
  • Jennifer Mueller
    • 29
  • Ivana Novaković
    • 15
  • Martin Paucar
    • 30
  • Henry Paulson
    • 31
  • Sheila A. Simpson
    • 27
  • Per Svenningsson
    • 30
  • Paul Tuite
    • 32
  • Jerrold Vitek
    • 32
  • Suppachok Wetchaphanphesat
    • 21
  • Charles Williams
    • 25
  • Michele Yang
    • 1
    • 33
  • Peter R. Schofield
    • 8
    • 9
  • João R. M. de Oliveira
    • 34
  • María-Jesús Sobrido
    • 2
    • 4
  • Daniel H. Geschwind
    • 1
    • 35
    • 36
    • 38
  • Giovanni Coppola
    • 1
    • 36
    • 37
  1. 1.Program in Neurogenetics, Department of Neurology, David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA
  2. 2.Fundación Pública Galega de Medicina Xenómica and Clinical University Hospital of Santiago de Compostela-SERGASSantiago de CompostelaSpain
  3. 3.Keizo Asami Laboratory and Biological Sciences Graduate ProgramFederal University of PernambucoRecifeBrazil
  4. 4.Center for Biomedical Research on Rare Diseases (CIBERER) Institute of Health Carlos IIIValenciaSpain
  5. 5.Department of Pathology and Laboratory ScienceCedars Sinai Medical CenterLos AngelesUSA
  6. 6.Department of Neurology, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  7. 7.Human Genome CenterUniversity of São PauloSão PauloBrazil
  8. 8.Neuroscience Research AustraliaSydneyAustralia
  9. 9.School of Medical SciencesThe University of New South WalesSydneyAustralia
  10. 10.Department of NeurologyUniversity of New MexicoAlbuquerqueUSA
  11. 11.Woodinville Psychiatric AssociationWoodinvilleUSA
  12. 12.Division of Genetics and MetabolismUniversity of Minnesota Medical CenterMinneapolisUSA
  13. 13.Centre for Healthy Brain Ageing, School of PsychiatryThe University of New South WalesSydneyAustralia
  14. 14.Department of NeurologyHospital of FigueresGironaSpain
  15. 15.Neurology ClinicUniversity Clinical CenterBelgradeSerbia
  16. 16.Department of NeurologyMonforte de Lemos Hospital-SERGASLugoSpain
  17. 17.The Center for Parkinson’s Disease & Related DisordersColumbia University Medical CenterNew YorkUSA
  18. 18.Department of NeurologyMichigan State UniversityEast LansingUSA
  19. 19.Pennsylvania State UniversityUniversity ParkUSA
  20. 20.Department of NeurologyHospital of BellvitgeBarcelonaSpain
  21. 21.Division of MedicineBuriram HospitalBuriramThailand
  22. 22.Klinikum AschaffenburgAschaffenburgGermany
  23. 23.The Movement Disorders Center and the Edomond J. Safra Program in Parkinson’s DiseaseToronto Western HospitalTorontoCanada
  24. 24.APHP, Center for Rare Disorders of the Calcium and Phosphorus MetabolismBicêtre-Paris-Sud Hospital; INSERM U986ParisFrance
  25. 25.Department of PediatricsUniversity of FloridaGainesvilleUSA
  26. 26.Department of NeurologyPenn State Milton S. Hershey College of MedicineOdessaUSA
  27. 27.Medical Genetics Group, School of Medicine & DentistryUniversity of AberdeenAberdeenUK
  28. 28.School of PsychiatryThe University of New South Wales and Black Dog InstituteSydneyAustralia
  29. 29.Division of Genetics and MetabolismUniversity of FloridaGainesvilleUSA
  30. 30.Translational Neuropharmacology, Clinical Neuroscience, Center for Molecular MedicineKarolinska Institute and Neurology Clinic, Karolinska HospitalStockholmSweden
  31. 31.Department of NeurologyUniversity of MichiganAnn ArborUSA
  32. 32.Department of NeurologyUniversity of Minnesota Medical CenterFairviewUSA
  33. 33.Department of PediatricsChildren’s Hospital Colorado and the University of Colorado DenverAuroraUSA
  34. 34.Neuropsychiatry Department and Keizo Asami LaboratoryFederal University of PernambucoRecifeBrazil
  35. 35.Department of Human Genetics, David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA
  36. 36.Department of Psychiatry and Semel Institute for Neuroscience and Human BehaviorUniversity of California Los AngelesLos AngelesUSA
  37. 37.Semel Institute for Neuroscience and Human BehaviorLos AngelesUSA
  38. 38.Program in Neurogenetics, Department of Neurology2306 Gonda, 695 Charles Young Drive SouthLos AngelesUSA

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