Analysis Of The FBXO7 Gene Mutation In Early-onset Pakinsonism Patients

Background and objective Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease, is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain, and the formation of alpha-synuclein-containing protein aggregates, termed Lewy bodies, in surviving neurons. PD is a sporadic, idiopathic disorder in most patients, but the identification of genetic mutations causing rare Mendelian forms of parkinsonism has provided novel clues for understanding of the disease pathogenesis. Recently, we characterized mutations in the F-box only protein 7 (FBXO7) gene, encoding the F-box protein 7 (FBXO7), as the cause of PARK15. PARK 15 used to be called Pallido-Pyramidal Disease (PPD) or Parkinsonian-Pyramidal Syndrome (PPS). It is associated with a series of symptoms that includes spasm state, hyperreflexia, and positive pyramidal signs besides the 3 classical PD symptoms (static tremor, bradykinesia, and rigidity). In 2008, Shojaee, etc, reported an Iranian pedigree, in which all affected individuals exhibited equinovarus deformity since childhood. The genome-wide linkage analysis on that pedigree with 500 K SNP arrays mapped the locus to chromosome 22, and a new disease-associated missense mutation (c.1132C→G) was found resulting in the nonconservative amino acid substitution of glycine for arginine at position 378(R378G) in the F-box protein 7.In 2009, Di Fonzo, etc, found an FBXO7 homozygous truncating mutation (Arg498Stop) in an Italian autosomal recessive early-onset parkinsonian pedigree, while compound heterozygous mutations (a splice-site IVS7+1G/T mutation and a missense Thr22Met mutation) presented in a Dutch family. Since then, gene FBXO7 was officially·designated as PARK15. Until now, no investigation of the mutation of FBXO7 in Chinese early-onset Parkinsonism patients has been done.Methods In this study, we executed polymerase chain reaction (PCR) combined with DNA direct sequencing on 135 Chinese early-onset Parkinsonism (including 23 unrelated probands with autosomal recessive early-onset Parkinsonism and 112 sporadic patients with early-onset Parkinson disease), and 200 normal Chinese people in order to screen the FBXO7 mutation.Results We found 10 sequence changes; of those,8 polymorphisms have been previously reported,2 others are newly discovered:-274G→C, C.A155G. No pathogenic mutation was found. All 10 base changes have been found in normal people. The difference between the frequency of those 10 polymorphisms in PD patients and the frequency in the control group was non-significant (P value> 0.05). We found that 2 polymorphisms are complete linkage with each other:Ivsl+116C→T (rs8136485) and Ivsl+272T→G (rs8137714). And 3 polymorphisms: c.G345A (pM115I, rs11107) in exon2, Ivs6-75T→C (rs738982) and c.C949T (pL317L, rs9726) in exon6 are complete linkage too. The D'=1 and the r2=1 when we analyzed them in this study.Conclusion FBXO7 mutations may be rare in Chinese early-onset Parkinsonism patients; those 10 polymorphisms found in this study have no effection in the expression of FBXO7 protein and the position of the protein either.