Analysis of exon dosage using MLPA in South African Parkinson's disease patients

Abstract

Genomic rearrangements (exon dosage) are common mutations reported in Parkinson's disease (PD) patients. In the present study, we aimed to investigate the prevalence of genomic rearrangements in 88 South African patients with predominantly early-onset PD (age-at-onset <or=50 years). The multiplex ligation-dependent probe amplification method was used to detect exon dosage changes. Two commercially available probe kits, SALSA P051 and P052, were used and together the kits consisted of probes for exons of alpha-synuclein, parkin, PINK1, DJ-1, LRRK2, UCH-L1, ATP13A2, LPA, TNFRSF9, CAV2, CAV1, GCH1, and two-point mutations. We identified exonic rearrangements in parkin and alpha-synuclein in 8% of South African patients from different ethnic groups. One patient had a whole-gene triplication of alpha-synuclein; representing only the fourth family with this mutation reported to date. We found six patients with parkin mutations who had either heterozygous duplications and deletions, or homozygous deletions. A false positive result of an exonic deletion detected in one patient turned out to be homozygous point mutation (Y258X) in PINK1. No exonic rearrangements were found in four of the PD genes; LRRK2, PINK1, DJ-1, and ATP13A2. Mutations in parkin were the predominant genetic cause; however, the frequency of exon dosage in our study group is low compared with previous studies. This indicates the possible involvement of other as yet unidentified PD genes in the development of the disease in the South African population.

Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

“…In conclusion, dosage mutations are relatively common in Brazilian early onset PD patients. The frequency observed by our study was similar to others from the literature [6,13,16]. PARKIN presented the majority of dosage alterations compared with the other known PD genes, as expected, while PINK1, SNCA and DJ-1 exon rearrangements were less common.…”

Early-onset parkinsonism caused by alpha-synuclein gene triplication: Clinical and genetic findings in a novel family

“…To our knowledge, SNCA triplications have been reported in only four extended families [3e6] and two single patients [7,8]. The patients reported so far developed an aggressive form of earlyonset parkinsonism, combined with additional non-motor signs, such as cognitive and autonomic dysfunctions.…”

Parkinson disease: Insights in clinical, genetic and pathological features of monogenic disease subtypes

“…Seemingly sporadic PD patients with SNCA duplication have also been reported (Ahn et al, 2008;Brueggemann et al, 2008;Troiano et al, 2008;Shin et al, 2010), although one must interpret these findings with caution since asymptomatic carriers have been reported in SNCA duplication families (Ahn et al, 2008;Nishioka et al, 2009). SNCA triplication causes a more severe phenotype with an earlier onset age, dysautonomia and dementia in comparison to SNCA duplication carriers Fuchs et al, 2007;Ibanez et al, 2009;Keyser et al, 2010). The presence of a homozygous SNCA duplication was reported by Ikeuchi and associates in an early-onset PD patient of Japanese origin, who developed dementia 7 years after disease onset (Ikeuchi et al, 2008).…”