Mutation in the SYNJ1 Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism

Carregando...
Imagem de Miniatura
Citações na Scopus
227
Tipo de produção
article
Data de publicação
2013
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY-BLACKWELL
Autores
QUADRI, Marialuisa
FANG, Mingyan
PICILLO, Marina
OLGIATI, Simone
BREEDVELD, Guido J.
GRAAFLAND, Josja
WU, Bin
XU, Fengping
ERRO, Roberto
AMBONI, Marianna
Citação
HUMAN MUTATION, v.34, n.9, p.1208-1215, 2013
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis. (C) 2013 Wiley Periodicals, Inc.
Palavras-chave
Parkinsonism, dystonia, dementia, SYNJ1, PINK1, gene, mutation
Referências
  1. Ben Gedalya T, 2009, TRAFFIC, V10, P218, DOI 10.1111/j.1600-0854.2008.00853.x
  2. Bonifacino JS, 2008, CURR OPIN CELL BIOL, V20, P427, DOI 10.1016/j.ceb.2008.03.009
  3. Bonifati Vincenzo, 2012, Parkinsonism Relat Disord, V18 Suppl 1, pS4, DOI 10.1016/S1353-8020(11)70004-9
  4. Bonifati V, 2003, SCIENCE, V299, P256, DOI 10.1126/science.1077209
  5. Cremona O, 1999, CELL, V99, P179, DOI 10.1016/S0092-8674(00)81649-9
  6. Di Fonzo A, 2009, NEUROLOGY, V72, P240, DOI 10.1212/01.wnl.0000338144.10967.2b
  7. Di Paolo G, 2006, NATURE, V443, P651, DOI 10.1038/nature05185
  8. Edvardson S, 2012, PLOS ONE, V7
  9. Fahn S, 2003, ANN NY ACAD SCI, V991, P1
  10. Hoffmann K, 2005, BIOINFORMATICS, V21, P3565, DOI 10.1093/bioinformatics/bti571
  11. HUGHES AJ, 1992, J NEUROL NEUROSUR PS, V55, P181, DOI 10.1136/jnnp.55.3.181
  12. Kitada T, 1998, NATURE, V392, P605
  13. Koroglu C, 2013, PARKINSONISM RELAT D, V19, P320, DOI 10.1016/j.parkreldis.2012.11.006
  14. Mani M, 2007, NEURON, V56, P1004, DOI 10.1016/j.neuron.2007.10.032
  15. Matta S, 2012, NEURON, V75, P1008, DOI 10.1016/j.neuron.2012.08.022
  16. McPherson PS, 1996, NATURE, V379, P353, DOI 10.1038/379353a0
  17. Milosevic I, 2011, NEURON, V72, P587, DOI 10.1016/j.neuron.2011.08.029
  18. Nalls MA, 2011, LANCET, V377, P641, DOI 10.1016/S0140-6736(10)62345-8
  19. Nemani VM, 2010, NEURON, V65, P66, DOI 10.1016/j.neuron.2009.12.023
  20. Paisan-Ruiz C, 2009, ANN NEUROL, V65, P19, DOI 10.1002/ana.21415
  21. Pankratz N, 2009, HUM GENET, V124, P593, DOI 10.1007/s00439-008-0582-9
  22. Perera RM, 2006, P NATL ACAD SCI USA, V103, P19332, DOI 10.1073/pnas.0609795104
  23. Popoff V, 2007, J CELL SCI, V120, P2022, DOI 10.1242/jcs.003020
  24. Ramirez A, 2006, NAT GENET, V38, P1184, DOI 10.1038/ng1884
  25. Ramjaun AR, 1996, J BIOL CHEM, V271, P24856
  26. Santoro L, 2011, NEUROGENETICS, V12, P33, DOI 10.1007/s10048-010-0259-0
  27. Shojaee S, 2008, AM J HUM GENET, V82, P1375, DOI 10.1016/j.ajhg.2008.05.005
  28. Singleton AB, 2013, MOVEMENT DISORD, V28, P14, DOI 10.1002/mds.25249
  29. Trempe JF, 2009, MOL CELL, V36, P1034, DOI 10.1016/j.molcel.2009.11.021
  30. UNGEWICKELL E, 1995, NATURE, V378, P632, DOI 10.1038/378632a0
  31. Valente EM, 2004, SCIENCE, V304, P1158, DOI 10.1126/science.1096284
  32. Vilarino-Guell C, 2011, AM J HUM GENET, V89, P162, DOI 10.1016/j.ajhg.2011.06.001
  33. Yim YI, 2010, P NATL ACAD SCI USA, V107, P4412, DOI 10.1073/pnas.1000738107
  34. Zimprich A, 2011, AM J HUM GENET, V89, P168, DOI 10.1016/j.ajhg.2011.06.008