論文 - 詳細
| RRC ID | 87991 |
|---|---|
| 著者 | O'Brien TJ, Navarro EP, Barroso C, Menzies L, Martinez-Perez E, Carling D, Brown AEX. |
| タイトル | High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations. |
| ジャーナル | BMC Biol |
| Abstract |
BACKGROUND:Genetic diagnosis is fast and cheap, challenging our capacity to evaluate the functional impact of novel disease-causing variants or identify potential therapeutics. Model organisms including C. elegans present the possibility of systematically modelling genetic diseases, yet robust, high-throughput methods have been lacking. RESULTS:Here we show that automated multi-dimensional behaviour tracking can detect phenotypes in 25 new C. elegans disease models spanning homozygous loss-of-function alleles and patient-specific single-amino-acid substitutions. We find that homozygous loss-of-function (LoF) mutants across diverse genetic pathways (including BORC, FLCN, and FNIP-2) exhibit strong, readily detectable abnormalities in posture, locomotion, and stimulus responses compared to wild-type animals. An smc-3 mutant strain-modelled by introducing a patient-identified missense change-exhibited developmental anomalies and distinct behavioural profiles even though complete loss of SMC-3 is lethal. In contrast, patient-derived missense mutations in another essential gene, tnpo-2, did not show a strong phenotype initially but it could be "sensitized" chemically (e.g., with aldicarb), potentially facilitating future drug screens. CONCLUSIONS:Our findings show that scalable behavioural phenotyping can capture a wide range of mutant effects-from strong to subtle-in patient-avatar worm lines. We anticipate that this standardized approach will enable systematic drug repurposing for rare genetic disorders as new disease variants are discovered. |
| 巻・号 | 23(1) |
| ページ | 281 |
| 公開日 | 2025-9-26 |
| DOI | 10.1186/s12915-025-02368-8 |
| PII | 10.1186/s12915-025-02368-8 |
| PMID | 41013606 |
| PMC | PMC12465487 |
| MeSH | Animals Behavior, Animal* Caenorhabditis elegans* / genetics Caenorhabditis elegans* / physiology Caenorhabditis elegans Proteins / genetics Disease Models, Animal* High-Throughput Screening Assays* / methods Humans Mutation* Phenotype* |
| リソース情報 | |
| 線虫 | tm1552 |