Mutations in ERBB4 That Disrupt The NRG-ErbB4 Pathway Cause Autosomal Dominant Familial ALS Type 19 (P1.083)
Bibliographic record
Abstract
OBJECTIVE: To identify a novel causative gene for FALS. BACKGROUND: Identification of novel causative genes for familial ALS (FALS) is a challenging task because of small family sizes and incomplete penetrance. Recent development of massively parallel sequencing method has allowed us to identify causative genes in these situations. DESIGN/METHODS: DNA samples from a Japanese FALS pedigree were obtained with informed consent. Linkage analysis was conducted with the assumption of autosomal-dominant mode of inheritance. Whole genome sequencing (WGS) was conducted on the proband, an affected sibling and the unaffected mother using a GAII Illumina Genome Analyzer. Novel non-synonymous variants were screened using DNA samples from 477 normal controls. Additional 364 FALS pedigrees and 818 SALS patients were included in mutational analysis. Functional studies were conducted using COS-7 cells expressing wild-type or mutant ErbB4. RESULTS: WGS revealed 382, 404 and 411 novel non-synonymous variants in the three individuals. Linkage analysis assuming complete penetrance revealed 3 candidate loci with the maximum LOD score of 1.8, where no novel non-synonymous variants were identified. Assuming incomplete penetrance (penetrance = 0.8), additional 7 loci were obtained with the LOD score >0.8, where only the variant c. 2780 G>A (p. R927Q) in ERBB4 was not identified in controls. Mutational analysis in additional samples revealed the same mutation in a Canadian pedigree and a de novo mutation c. 3823C.>T (p.R1275W) in a Japanese SALS patient. Clinical presentations of patients with mutations were those of typical ALS diagnosed as definite or probable ALS. Functional analysis revealed decreased level of autophosphorylation upon stimulation by NRG-1. CONCLUSIONS: This study revealed that mutations in ERBB4 that disrupt the NRG-ErbB4 pathway cause autosomal dominant ALS (ALS19). This study provides a new insight into ALS pathogenesis and paves a way for development of innovative therapeutic strategies such as upregulating ErbB4 functions using NRGs or their agonists. Study Supported by: KAKENHI, the Global COE Program and a Grant-in-Aid [H23-Jitsuyoka (Nanbyo)-Ippan-004].
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".