These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.
Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as new causal Parkinson's disease (PD) genes, with the VPS35 D620N and EIF4G1 R1205H mutations being identified in both autosomal dominant late-onset familial and sporadic PD patients.
Complete exonic regions of these 2 genes were resequenced in 15 well-characterized PD families; the reported p.Asp620Asn in VPS35 and p.Arg1205His in EIF4G1 mutations were screened in an additional 54 familial and 251 sporadic PD cases, and no mutations were observed.
The Asp620Asn mutation in the vacuolar protein sorting protein 35 (VPS35) gene and the Arg1205His mutation in the eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) gene were identified in autosomal dominant late-onset familial and sporadic Parkinson disease (PD) patients in a Caucasian population.
In order to assess the frequency of the reported mutation and to search for other possible disease-causing variants in this gene, we sequenced all 17 exons of VPS35 in 96 familial PD cases, and exon 15 (in which the reported mutation is found) in an additional 64 familial PD cases, 175 young-onset PD cases, and 262 sporadic, neuropathologically confirmed PD cases.
Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain.