neurogenetics

, Volume 10, Issue 3, pp 265–270 | Cite as

A new complex homozygous large rearrangement of the PINK1 gene in a Sudanese family with early onset Parkinson’s disease

  • Cécile Cazeneuve
  • Channkanira Sân
  • Salah A. Ibrahim
  • Maowia M. Mukhtar
  • Musa M. Kheir
  • Eric LeGuern
  • Alexis Brice
  • Mustafa A. Salih
Short Communication

Abstract

PARK2 and PINK1 gene mutations are involved in recessive early onset Parkinson’s disease (EOPD). In order to determine the causative mutations in three affected sibs from a consanguineous Sudanese family with EOPD, multiplex ligation-dependent probe amplification was performed and revealed that the patients were homozygous for a deletion of PINK1 exons 4 to 8. Breakpoint analysis revealed a complex rearrangement combining a large deletion and the insertion of a sequence duplicated from the DDOST gene intron 2, located near the PINK1 gene. As breakpoint sequences displayed only three base pairs of homology, this rearrangement may result from Fork Stalling and Template Switching mechanism. This third large rearrangement of PINK1 enlarges the mutation spectrum and, together with recent published data in Tunisian patients with EOPD, points out that PINK1 gene analysis, including search for large rearrangement, should be considered in early onset recessive PD patients, particularly those from Arab origin.

Keywords

Early onset Parkinson’s disease Autosomal recessive PINK1 PARK6 Complex rearrangement Fork Stalling and Template Switching 

References

  1. 1.
    Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos E, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson W, Lazzarini A, Duvoisin R, Di Iorio G, Golbe L, Nussbaum R (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047. doi:10.1126/science.276.5321.2045 PubMedCrossRefGoogle Scholar
  2. 2.
    Paisán-Ruíz C, Jain S, Evans E, Gilks W, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil A, Khan N, Johnson J, Martinez J, Nicholl D, Carrera I, Pena A, de Silva R, Lees A, Martí-Massó J, Pérez-Tur J, Wood N, Singleton A (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600. doi:10.1016/j.neuron.2004.10.023 PubMedCrossRefGoogle Scholar
  3. 3.
    Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608. doi:10.1038/33416 PubMedCrossRefGoogle Scholar
  4. 4.
    Valente E, Abou-Sleiman P, Caputo V, Muqit M, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio A, Healy D, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks W, Latchman D, Harvey R, Dallapiccola B, Auburger G, Wood N (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160. doi:10.1126/science.1096284 PubMedCrossRefGoogle Scholar
  5. 5.
    Bonifati V, Rizzu P, van Baren M, Schaap O, Breedveld G, Krieger E, Dekker M, Squitieri F, Ibanez P, Joosse M, van Dongen J, Vanacore N, van Swieten J, Brice A, Meco G, van Duijn C, Oostra B, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259. doi:10.1126/science.1077209 PubMedCrossRefGoogle Scholar
  6. 6.
    Lücking C, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi B, Meco G, Denèfle P, Wood N, Agid Y, Brice A (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342:1560–1567. doi:10.1056/NEJM200005253422103 PubMedCrossRefGoogle Scholar
  7. 7.
    Leutenegger A, Salih M, Ibáñez P, Mukhtar M, Lesage S, Arabi A, Lohmann E, Dürr A, Ahmed A, Brice A (2006) Juvenile-onset Parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain of PINK1. Arch Neurol 63:1257–1261. doi:10.1001/archneur.63.9.1257 PubMedCrossRefGoogle Scholar
  8. 8.
    Li Y, Tomiyama H, Sato K, Hatano Y, Yoshino H, Atsumi M, Kitaguchi M, Sasaki S, Kawaguchi S, Miyajima H, Toda T, Mizuno Y, Hattori N (2005) Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism. Neurology 64:1955–1957. doi:10.1212/01.WNL.0000164009.36740.4E PubMedCrossRefGoogle Scholar
  9. 9.
    Marongiu R, Brancati F, Antonini A, Ialongo T, Ceccarini C, Scarciolla O, Capalbo A, Benti R, Pezzoli G, Dallapiccola B, Goldwurm S, Valente E (2007) Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum. Hum Mutat 28:98. doi:10.1002/humu.9472 PubMedCrossRefGoogle Scholar
  10. 10.
    Lee J, Carvalho C, Lupski J (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235–1247. doi:10.1016/j.cell.2007.11.037 PubMedCrossRefGoogle Scholar
  11. 11.
    Bellanné-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, Douillard C, Dubois-Laforgue D, Dusselier L, Gautier J, Jadoul M, Laloi-Michelin M, Jacquesson L, Larger E, Louis J, Nicolino M, Subra J, Wilhem J, Young J, Velho G, Timsit J (2005) Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes 54:3126–3132. doi:10.2337/diabetes.54.11.3126 PubMedCrossRefGoogle Scholar
  12. 12.
    Benamer H, de Silva R, Siddiqui K, Grosset D (2008) Parkinson’s disease in Arabs: a systematic review. Mov Disord 23:1205–1210. doi:10.1002/mds.22041 PubMedCrossRefGoogle Scholar
  13. 13.
    Choi J, Woo M, Ma H, Kang S, Sung Y, Yong S, Chung S, Kim J, Shin H, Lyoo C, Lee P, Baik J, Kim S, Park M, Sohn Y, Kim J, Kim J, Lee M, Lee M, Kim D, Kim Y (2008) Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics 9:263–269. doi:10.1007/s10048-008-0138-0 PubMedCrossRefGoogle Scholar
  14. 14.
    Gelmetti V, Ferraris A, Brusa L, Romano F, Lombardi F, Barzaghi C, Stanzione P, Garavaglia B, Dallapiccola B, Valente E (2008) Late onset sporadic Parkinson’s disease caused by PINK1 mutations: clinical and functional study. Mov Disord 23:881–885. doi:10.1002/mds.21960 PubMedCrossRefGoogle Scholar
  15. 15.
    Ishihara-Paul L, Hulihan M, Kachergus J, Upmanyu R, Warren L, Amouri R, Elango R, Prinjha R, Soto A, Kefi M, Zouari M, Sassi S, Yahmed S, El Euch-Fayeche G, Matthews P, Middleton L, Gibson R, Hentati F, Farrer M (2008) PINK1 mutations and parkinsonism. Neurology 71:896–902. doi:10.1212/01.wnl.0000323812.40708.1f PubMedCrossRefGoogle Scholar
  16. 16.
    Kumazawa R, Tomiyama H, Li Y, Imamichi Y, Funayama M, Yoshino H, Yokochi F, Fukusako T, Takehisa Y, Kashihara K, Kondo T, Elibol B, Bostantjopoulou S, Toda T, Takahashi H, Yoshii F, Mizuno Y, Hattori N (2008) Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. Arch Neurol 65:802–808. doi:10.1001/archneur.65.6.802 PubMedCrossRefGoogle Scholar
  17. 17.
    Prestel J, Gempel K, Hauser T, Schweitzer K, Prokisch H, Ahting U, Freudenstein D, Bueltmann E, Naegele T, Berg D, Klopstock T, Gasser T (2008) Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation. J Neurol 255:643–648. doi:10.1007/s00415-008-0763-4 PubMedCrossRefGoogle Scholar
  18. 18.
    Weng Y, Chou Y, Wu W, Lin K, Chang H, Yen T, Chen R, Wey S, Lu C (2007) PINK1 mutation in Taiwanese early-onset parkinsonism : clinical, genetic, and dopamine transporter studies. J Neurol 254:1347–1355. doi:10.1007/s00415-007-0534-7 PubMedCrossRefGoogle Scholar
  19. 19.
    Ibáñez P, Lesage S, Lohmann E, Thobois S, De Michele G, Borg M, Agid Y, Dürr A, Brice A (2006) Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 129:686–694. doi:10.1093/brain/awl005 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Cécile Cazeneuve
    • 1
  • Channkanira Sân
    • 1
  • Salah A. Ibrahim
    • 2
  • Maowia M. Mukhtar
    • 3
  • Musa M. Kheir
    • 4
  • Eric LeGuern
    • 1
    • 5
    • 6
  • Alexis Brice
    • 1
    • 5
    • 6
  • Mustafa A. Salih
    • 7
  1. 1.Département de Génétique et Cytogénétique, U.F. de NeurogénétiqueAssistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-SalpêtrièreParisFrance
  2. 2.Department of Pediatrics, Faculty of MedicineUniversity of KhartoumKhartoumSudan
  3. 3.Institute of Endemic DiseasesUniversity of KhartoumKhartoumSudan
  4. 4.Department of Medicine, Faculty of MedicineUniversity of KhartoumKhartoumSudan
  5. 5.INSERM UMR_S 679 Neurologie & Thérapeutique ExpérimentaleGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  6. 6.UMR_S679UPMC Univ Paris 06ParisFrance
  7. 7.Division of Pediatric Neurology, College of MedicineKing Saud UniversityRiyadhSaudi Arabia

Personalised recommendations