Athanasiou-Fragkouli, A. | Search bioRxiv

bioRxiv2022

Molecular basis of FAAH-OUT-associated human pain insensitivity

Chronic pain affects millions of people worldwide. Studying pain insensitive individuals helps to identify novel analgesic strategies. Here we report how the recently discovered FAAH-OUT lncRNA-encoding gene, which was found from studying a pain insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed and a platform for development of future gene and small molecule therapies.

neuroscience↗

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↗