Early onset leprosy reveals a joint effect of <i>LRRK2</i> and <i>NOD2</i> variants
Bibliographic record
Abstract
Abstract Leprosy, caused by Mycobacterium leprae , has a long incubation period and cases with age-of-onset <5 years are rare. Here, we studied a three-generational multiplex leprosy family which included monozygotic twins age <24 months suffering from paucibacillary leprosy. Whole genome sequencing identified a homozygous double mutation in the LRRK2 gene (N551K, R1398H) and a heterozygous mutation in NOD2 (R702W) as candidate variants underlying the early onset phenotype in the twins. The same amino acid substitutions had previously been identified as shared risk-modulating factors for Crohn’s disease and Parkinson’s disease. To evaluate the functional impact of the LRRK2 mutations, we employed genome editing in RAW264.7 cells. Cells expressing the LRRK2 variants displayed reduced respiratory burst and apoptosis following mycobacterial challenge. Moreover, the BCG-induced respiratory burst was significantly lower in LRRK2 wild-type-expressing cells transfected with NOD2 R702W compared with NOD2 wild-type constructs. Employing co-immunoprecipitation, we showed that LRRK2 and NOD2 wild-type proteins interact in RAW cells. This interaction was independent of the LRRK2 variants but strongly reduced for NOD2 R702W. However, N-glycolyl MDP-triggered RIP2 phosphorylation and NF-kB activation were additively reduced by both LRRK2 and NOD2 mutations. Finally, we observed a joint effect of LRRK2 and NOD2 variants on cytokine/chemokine secretion with the most significant reduction of secretion observed for the mutant genotypes carried by the twins. These data demonstrated the pleiotropic effects of LRRK2 and NOD2 in response to mycobacterial infection consistent with a role of the identified mutations in the development of early onset leprosy. One Sentence Summary Variants of NOD2 and LRRK2 shared between early onset leprosy, Parkinson’s and Crohn’s disease jointly impact the anti-mycobacterial host response.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".