rs2298298

We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset< 50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p. G2019S. We screened for LRRK2 p. G2019S in the entire PD cohort using a genotyping assay. The PINK1 p. R501Q functional analysis was conducted.

2021 · LM Milanowski, O Oshinaike

La Tunisie a vu une grande variete d'envahisseurs et de migrants allant de la population berbere autochtone aux Arabes et Europeens. Cette region est caracterisee par les grands pedigrees, les faibles taux de migration et les taux eleves de consanguinite qui augmentent le risque des maladies autosomiques recessives y compris les maladies neuro-degeneratives. Dans notre pays, la prevalence de la maladie de Parkinson (MP) augmente jusqu’a 43/100000 personnes et devient un probleme de sante majeur. La MP est une maladie neuro-degenerative dont la forme idiopathique debute en moyenne vers 60 ans. Au cours des 20 dernieres annees, plusieurs genes ont ete identifies chez des patients qui ont developpe leurs premiers symptomes avant l’âge de 40 ans. Notre etude a montre que la structure genetique de la MP en Tunisie est distincte des autres populations, puisque plus de 50% des cas avaient une origine genetique. La frequence des formes monogeniques chez les patients avec un âge de debut tardif de la MP etait relativement elevee et similaire a celle des patients avec un âge de debut precoce. Ces formes etaient essentiellement dues a la mutation LRRK2-p.G2019S (identifiee chez 44.4% des cas) qui s'avere etre une mutation fondatrice apparue chez un seul ancetre commun d’origine berbere. Sur le plan clinique, nous avons montre que les patients porteurs de la mutation LRRK2-p.G2019S avaient un âge de debut de la MP plus precoce mais avec un phenotype plus benin que celui des formes idiopathiques. Une deuxieme mutation fondatrice d’origine berbere (p.Q456*) a ete identifiee sur le gene PINK1. La frequence elevee inhabituelle des mutations sur ce gene peut etre limitee a la population tunisienne berbere. Nos resultats ont aussi confirme que les mutations sur le gene PARK2 et sur le gene GBA ne constituent pas un facteur de risque frequent de la MP en Tunisie. En plus de ces mutations sur les genes connus, nous avons identifie 4 nouveaux genes candidats dans la MP. Cette structure genetique particuliere de la MP en Tunisie pourrait etre principalement le resultat de l'origine historique berbere de notre population Tunisienne. (Tunisia has seen a wide variety of invaders and migrants ranging from the indigenous Berber population to Arabs and Europeans. This region is characterized by high pedigrees, low migration rates and high inbreeding rates which increase the risk of autosomal recessive diseases including neurodegenerative diseases. In our country, the prevalence of Parkinson's disease (PD) increases to 43/100,000 people and becomes a major health problem. PD is a neurodegenerative disease whose idiopathic form begins on average around the age of 60. Over the past 20 years, several genes have been identified in patients who developed their first symptoms before the age of 40.Our study showed that the genetic structure of PD in Tunisia is distinct from other populations, since more than 50% of cases had a genetic origin. The frequency of monogenic forms in patients with a late onset age of PD was relatively high and similar to that of patients with an early onset age. These forms were essentially due to the LRRK2-p.G2019S mutation (identified in 44.4% of cases) which turns out to be a founding mutation that appeared in a single common ancestor of Berber origin. Clinically, we showed that patients carrying the LRRK2-p.G2019S mutation had an earlier age of onset of PD but with a more benign phenotype than that of idiopathic forms. A second founding mutation of Berber origin (p.Q456*) was identified in the PINK1 gene.The unusual high frequency of mutations in this gene may be limited to the Tunisian Berber population. Our results also confirmed that mutations in the PARK2 gene and the GBA gene do not constitute a frequent risk factor for PD in Tunisia. In addition to these mutations in known genes, we identified 4 new candidate genes in PD. This particular genetic structure of PD in Tunisia could be mainly the result of the historical Berber origin of our Tunisian population.In addition to these mutations in known genes, we identified 4 new candidate genes in PD. This particular genetic structure of PD in Tunisia could be mainly the result of the historical Berber origin of our Tunisian population.In addition to these mutations in known genes, we identified 4 new candidate genes in PD. This particular genetic structure of PD in Tunisia could be mainly the result of the historical Berber origin of our Tunisian population.)

2019 · Sawssan Ben Romdhan

Loss-of-function mutation in PINK1 is known for causing autosomal recessive early onset Parkinsonism accounting approximately 6.5% of PD cases. Recently, PINK1 has also been shown to cause Parkinson's disease (PD) in eastern India. Present study is aimed to see its contribution in north-Indian PD patients. A total of 106 PD patients and 60 ethnically matched healthy controls were included in the study. All the patients were screened for mutation in PINK1 by direct DNA sequence analysis of the PCR amplicons covering all exons and exon-intron boundaries. Identified novel variant was reconfirmed by DNA sequencing of 10 randomly selected TA clones containing the variant amplicon. In vitro functional assay of the mutant protein was performed by transfecting COS-7 cell line with wild type and mutant (created by site-directed-mutagenesis) cDNA construct of PINK1 fused to N' terminal GFP followed by western blot analysis. Two potentially pathogenic, one being novel (p.Q267X) and 6 other apparently non-pathogenic variants were identified. Western blot analysis reveals production of truncated PINK1 fusion protein of ∼55kDa in p.Q267X mutant instead of 82/93kDa of wild type PINK1 fusion protein (molecular weight of GFP is ∼27kDa). Our study concludes that PINK1 variants are prevalent for causing Parkinson's disease (PD) in India, as revealed by the occurrence of 1.8% (2/106) in PD patients from north Indian population. The novel homozygous variant of PINK1 (c.799C>T) reported here is the plausible cause for disease manifestation in this patient. Future study, however, would be helpful to understand the functional mechanism how this premature PINK1 protein (p.Q267X) responds to cellular stress leading to the PD pathophysiology.

2015 · Tamali Halder, Janak Raj, Vivek Sharma, Parimal Das

To determine the frequency of mutations in PINK1 in Chinese Han people with sporadic early-onset Parkinsonism (EOP).

2011 · Xuewei Zhang, Hainan Zhang, Bing Liao, Jifeng Guo, Kun Xia, Beisha Tang