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 SYNJ1 ORF 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.
Mutation in the SYNJ1Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism / Marialuisa Quadri;Mingyan Fang;Marina Picillo;Simone Olgiati;Guido J. Breedveld;Josja Graafland;Bin Wu;Fengping Xu;Roberto Erro;Marianna Amboni;Sabina Pappatà;Mario Quarantelli;Grazia Annesi;Aldo Quattrone;Hsin F. Chien;Egberto R. Barbosa;Ben A. Oostra;Paolo Barone;Jun Wang;Vincenzo Bonifati; International Parkinsonism Genetics Network:Bonifati V; Maat-Kievit A; Rood J; Boon A; van de Warrenburg B; Delnooz C; Rietveld A; Bloem B; Ferreira J; Correia Guedes L; Tolosa E; Janssens S; Emre M; Hanagasi H; Bilgic B; Elibol B; Socal M; Jardim L; Chien HF; Barbosa ER; Lu CS; Wu-Chou YH; Yeh TH; Atadzhanov M; Kelly P; Lopiano L; Tassorelli C; Pacchetti C; Nappi G; Riboldazzi G; Bono G; Padovani A; Borroni B; Raudino F; Di Fonzo A; Volonte A; Fincati E; Bertolasi L; Tinazzi M; Bonizzato A; Ferracci C; Dalla Libera A; Cortelli P; Capellari S; Marini P; Massaro F; Federico A; Taglia I; Battisti C; Marconi R; Onofrj M; Thomas A; Vanacore N; Meco G; Fabbrini G; Fabrizio E; Manfredi M; Berardelli A; Stocchi F; Vacca L; De Michele G; Criscuolo C; Santoro L; Filla A; De Mari M; Dell C; Iliceto G; Lamberti P; Toni V; Trianni G; Gagliardi M; Annesi G; Quattrone A; Saddi V; Francesco S; Saddi V; Cossu G; Melis M.. - In: HUMAN MUTATION. - ISSN 1059-7794. - STAMPA. - 34:(2013), pp. 1208-1215. [10.1002/humu.22373]
Mutation in the SYNJ1Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism
CORTELLI, PIETRO;CAPELLARI, SABINA;
2013
Abstract
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 SYNJ1 ORF 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
