Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease

Abstract

Vinicius Fava, PhD. 1001 Blvd Decarie; Site Glen Block E, Bioinformatics suíte Rm ES1.5561.Montreal, QC, H4A 3J1. Canada. vinicius.medeirosfava@mail.mcgill.ca † Drs. Fava and Schurr contributed equally to this article. Abstract:Type-1 reactions (T1Rs) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the gene-wise enrichment of rare protein altering variants in seven genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy-patients of which 237 were T1R-affected and 237 were T1Rfree matched controls. Gene-wise enrichment of nonsynonymous variants was tested with both kernel based (SKAT) and burden methods. Of the seven genes tested two showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (p SKAT -O= 1.6x10 -4 ). This gene-wise association was driven almost entirely by the gain of function variant R1628P (p = 0.004; OR = 0.29). The second gene-wise association was found for the Parkin coding gene PRKN (formerly PARK2)where seven rare variants were enriched in T1R-affected cases (p SKAT -O = 7.4x10 -5 ). Mutations in both PRKN and LRRK2 are known causes of Parkinson's Disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that nonsynonymous T1R-risk mutations in Parkin were enriched for amino acid mutations implicated in PD (p = 1.5x10 -4 ). Hence, neuro-inflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping mechanisms of pathogenicity.

Necrosis drives susceptibility toMycobacterium tuberculosisin POLG mtDNA mutator mice

“…Most of these studies looked at patients with leprosy, which is caused by Mycobacterium leprae, a close cousin of Mtb. Mutations in genes like Park2, which encodes the mitophagy factor Parkin (52,53), Tfam, which encodes a histone-like protein of the mitochondrial genome (11), as well as Polg (11) have been linked to leprosy susceptibility or severity of disease. The Mtb phenotype we report is consistent with GWAS that identified a human SNP in POLG associated with multibacillary leprosy-a form of the disease characterized by high bacterial loads in lesions (11).…”