Biology subjects

Rizig, M.

Publications and source records attributed to Rizig, M..

4 recordsLinked to original sources

bioRxiv2020

Negative screening for 12 rare LRRK2 pathogenic variants in a cohort of Nigerians with Parkinson disease

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most commonly identified genetic variants in familial and sporadic Parkinson’s disease (PD). Over three hundred LRRK2 variants have been described in the literature, of which at least 17 have a confirmed or probable pathogenic role in PD. The distribution of these rare pathogenic variants has been shown to be different among ethnic groups including Caucasians, Latin Americans and East and South Asians. However, to date no PD-related LRRK2 pathogenic variant has been described in persons of black African ancestry within or outside Africa. We previously reported that the LRRK2 p.gly2019ser mutation was not found in 126 PD patients and 55 controls from Nigeria. Using Kompetitive Allele-Specific Polymerase chain reaction (KASP), we screened a new cohort of 92 Nigerians with PD and 210 healthy ethnically matched controls for 12 rare LRRK2 variants (which have been shown to be pathogenic in other ethnic populations) including: p.gly2019ser, p.Arg1441His, p.Gly2385Arg, p.Ala419Val, p.Arg1628Pro, p.Pro755Leu, p.Ile2020Thr and Tyr1699Cys. All 12 rare variants were absent in PD patients and controls from this cohort. These results endorse our previous findings and confirm that rare LRRK2 pathogenic variants reported in Caucasians, Asians and persons of mixed ancestry are absent in West Africans. Applying next generation sequencing technologies in future studies is necessary to explore possible novel LRRK2 variants indigenous to black Africans.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2019

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinsons disease

ObjectiveTo assess genetic modifiers of Parkinsons disease (PD) age at onset (AAO) penetrance in individuals carrying common and rare LRRK2 risk alleles\n\nMethodsWe analysed reported genetic modifier DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using linear regression of AAO. We meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3 and is associated with PD. We analysed the effect of the rs11578699 VAMP4 variant on pG2019S penetrance in 786 LRRK2 p.G2019S heterozygotes. We also evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).\n\nResultsThere was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699. Our linear regression AAO of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (beta = -1.19, p = 0.55, n =708). Meta-analysis with previously published data did not indicate a significant effect on AAO (beta = -2.21, p = 0.083, n = 1304), but there was significant heterogeneity in the analyses of new and previously published data. VAMP4 rs11578699 was nominally associated with AAO in patients dichotomized by the common LRRK2 risk variant rs10878226 (beta=1.68, se=0.81 p=0.037).\n\nInterpretationAnalysis of DNM3 in previously unpublished data does not show an interaction between DNM3 and LRRK2 G2019S for AAO, however the inter-study heterogeneity may indicate ethnic-specific effects of DNM3 rs2421947. Analysis of sporadic PD patients stratified by the PD risk variant rs10878226 indicates a possible interaction between LRRK2 and VAMP4.

genetics↗

bioRxiv2018

Leucine Rich Repeat Kinase 2 (LRRK2) Gly2019Ser Mutation Is Absent In A Second Cohort Of Nigerian Africans With Parkinson Disease.

To date the LRRK2 p.G2019S mutation remains the most common genetic cause of Parkinson disease (PD) worldwide. It accounts for up to 6% of familial and approximately 1.5% of sporadic cases. LRRK2 has a kinase enzymatic domain which provides an attractive potential target for drug therapies and LRRK2 kinase inhibitors are in development. Prevalence of the p.G2019S has a variable ethnic and geographic distribution, the highest was reported among Ashkenazi Jews (30% in patients with familial PD, 14% in sporadic PD, 2.0% in controls) and North African Berbers (37% in patients with familial PD, 41% in sporadic PD, and 1% in controls). Little is known about the frequency of the LRRK2 p.G2019S among populations in Sub Saharan Africa. Our group and others previously reported that the p.G2019S is absent in a small cohort from Nigerian PD patients and controls. Here we used Kompetitive Allele Specific PCR (KASP) assay to screen for the p.G2019S in a larger cohort of Black African PD patients (n =126) and healthy controls (n = 55) from Nigeria. Our analysis confirmed that all patients and controls are negative for the p.G2019S mutation. This report provides further evidence that the LRRK2 p.G2019S is not implicated in PD in black populations from Nigeria and support the notion that p.G2019S mutation originated after the early human dispersal from sub-Saharan Africa. Further studies using larger cohorts and advance sequencing technology are required to underpin the genetic causes of PD in this region.

genetics↗

bioRxiv2018

MALARIA and BURKITT′S LYMPHOMA: An IN SILICO ANALYSIS of GENE EXPRESSION LINKS BETWEEN MALARIA and BURKITT’S LYMPHOMA and POTENTIAL ANTICANCER ACTIVITY of ARTEMISININ DERIVATIVES

BackgroundBurkitts lymphoma (BL) is an aggressive form of B-cell non-Hodgkin lymphoma. Endemic subtype of the disease showed a remarkable statistical and epidemiological association with malaria infection. Despite the numerous studies performed to explain this association; molecular mechanisms underlie such coincidence still remain unclear. Dissecting molecular mechanisms which link Malaria infection and Burkitts lymphoma can provide insights about reported anticancer action of certain antimalarial drugs, namely artemisinin derivatives.\n\nMethodsHere we applied an integrative approach to investigate for potential links between malaria infection and endemic Burkitts lymphoma regarding their gene expression, and further explore common molecular mechanisms through which artemisinin compounds might act in endemic Burkitts lymphoma. Using gene expression data of malaria (Plasmodium falciparum infected erythroblasts) and endemic Burkitts lymphoma from Gene Expression Omnibus database, expression patterns in the two conditions were examined through clustering analysis using Self Organizing Maps, and then by significance testing of differentially expressed genes in each condition followed by Functional annotation using Gene Ontology clustering and Pathways analysis.\n\nResultsClustering analysis identified a significant overlap between the expression patterns in endemic Burkitts lymphoma and Plasmodium falciparum infected cells. Four out of the 12 identified clusters contained genes with similar expression patterns in both conditions. Differential expression analysis identified 1689 genes as significantly differentially expressed in endemic Burkitts lymphoma and 405 in malaria. Those genes were found to be related to important Gene Ontology terms and pathways. Interestingly 65% of the identified pathways in Malaria were overlapped with those identified in endemic Burkitts lymphoma. Several of these pathways reported to be related to actions of artemisinin derivatives.\n\nConclusionOur In-silico analysis showed a significant molecular convergence between endemic Burkitts lymphoma and malaria. A number of 43pathways which demonstrated enrichment in tumour were shared with Plasmodium falciparum infected erythrocytes. Such pathways represent potential targets for antimalarial drugs to exert therapeutic effects in such malignancy.

bioinformatics↗