Mutation in theSYNJ1Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism

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.

Phosphoinositides in endocytosis

“…Dysfunction of OCRL is associated with endocytic defects in oculocerebrorenal syndrome of Lowe and in Dent's disease [84,86], inherited kidney disorders as well as with defective cytokinesis [143]. Trisomy for the OCRL-related brain-enriched endocytic PI(4,5)P 2 phosphatase synaptojanin 1 is linked to early endosomal defects and mental retardation in Down syndrome [144] and in Parkinson's disease [145,146]. Conversely, accumulation of Aβ leads to decreased PI(4,5)P 2 levels, a phenotype rescued by synaptojanin 1 haploinsufficiency in mice [147,148].…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…Mutations in synaptojanin have also been linked to bipolar disorder and autosomal recessive, early-onset Parkinsonism (Saito et al, 2001;Krebs et al, 2013;Quadri et al, 2013).…”

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

“…The first gene that was identified was SNCA (synuclein, a [non A4 component of amyloid precursor]), in an Italian family with PD, 33 followed by the identification of the PARK2, 34 PINK1 35 and PARK7/DJ-1 36 genes in young onset recessively inherited PD. Additional autosomal recessive mutations that lead to atypical parkinsonism syndromes were identified in the genes ATP13A2, 37 ATP6AP2, 38 and SYNJ1, 39,40 and mutations in DNAJC13 were suggested to cause autosomal dominant familial PD. 41 Disease-causing mutations with reduced penetrance were also identified in familial settings and cohort studies in the LRRK2 [42][43][44][45] and GBA 46 genes, which are now recognized as the 2 most common genetic causes of PD worldwide.…”

“…133 In addition, knockdown or mutated VPS35 in neuronal cell cultures leads to reduced colocalization of the M6PR with the Golgi apparatus and with late endosome/lysosome markers. 17 Interestingly, 2 additional genes that cause rare autosomal recessive atypical parkinsonism, ATP6AP2, 38 and SYNJ1, 39,40 and the dominant PD gene DNAJC13, 41 are also involved in the endosomal pathway. Similar to VPS35, DNAJC13 is also associated with the WASH complex by binding to the FAM21 protein.…”