Journal Article

Allele-dependent interaction of LRRK2 and NOD2 in leprosy

Tao, Shao, Manry, Jérémy, Cobat, Aurélie, Correa-Macedo, Wilian, Dallmann-Sauer, Monica, Pinheiro, Roberta Olmo, Schurr, Erwin, Prata, Rhana Berto da Silva, Mira, Marcelo T., Xu, Yong Zhong, Lara, Flavio Alves, Gomes, Tiago Araujo, Abel, Laurent, Fava, Vinicius M., Alcaïs, Alexandre, Probst, Christian M., da Costa, Ana Lúcia França

2023

Overview

Leprosy, caused by Mycobacterium leprae , rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn’s disease and Parkinson’s disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age groups / Alleles / Amino acids / Analysis / Apoptosis / BCG / BCG vaccines / Biology and Life Sciences / Candidates / Care and treatment / Chemokines / Child / Confocal microscopy / Crohn's disease / Diagnosis / DNA sequencing / Gene mutations / Gene sequencing / Genes / Genetic aspects / Genetic Predisposition to Disease / Genomes / Genomics / Genotype / Genotype & phenotype / Genotypes / Health aspects / Health risk assessment / Humans / Immunoprecipitation / Infectious diseases / Inflammatory bowel disease / Leprosy / Leprosy - genetics / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics / LRRK2 protein / Macrophages / Medicine and Health Sciences / Monocytes / Movement disorders / Mutation / Neurodegenerative diseases / NF-κB protein / NOD2 protein / Nod2 Signaling Adaptor Protein - genetics / Nucleotide sequencing / Parkinson's disease / Proteins / Research and Analysis Methods / Respiratory burst / Scientific equipment and supplies industry / Twins / Whole genome sequencing