Can public evidence prioritize testable drug-repurposing hypotheses for BUB1B L737* and N1002K?
The reading order of the MVA · BUB1B case as a trail: the two variant questions, the evidence records behind each gate, the three stated hypotheses, the gaps that keep them conditional, and the measurements proposed next. Every step links to the records, publications and graph nodes it rests on; nothing is concluded beyond what they say.
Curated: Case page reading order: overview → 01 Summary and findings → 02 Questions → evidence records → 05 October 24 revision → 06 Future validation · updated
01
Question
Two BUB1B variants, two molecular questions
L737* introduces a premature stop codon, an RNA and translation question. N1002K is a missense change in the kinase region, a protein stability and function question. Both sit in BUB1B, which encodes the spindle assembly checkpoint component BUBR1, in a case of mosaic variegated aneuploidy. The guiding question of the case: can public evidence prioritize testable drug-repurposing hypotheses?
Source: Case page, overview ("The question", "Case at a glance")
02
Evidence
The RNA gate for L737*
Three records organise the RNA question. The NMD-first audit finds a related 731X construct that motivates testing whether a truncated product retains function, while the exact L737* experiment has not been performed. The readthrough reanalysis finds no exact L737* context in the 5,837-PTC table. The transfer audit shows that endogenous-protein readthrough evidence comes from another gene and stop context.
Source: Case page, question "RNA availability"; records MVA-L737-NMD-FIRST-001, MVA-RT-002, MVA-RT-TRANSFER-009 and the publications they cite
03
Hypothesis
Preserving RNA leaves the stop codon
Stated hypothesis of the case: NMD modulation alone cannot establish a useful protein product; readthrough needs exact-context and functional validation. It remains proposed. The gaps it depends on are listed with it.
Source: Case page, 01 Summary and findings (card "L737* / RNA & translation")
04
Evidence
The function gate for N1002K
The equal-expression audit locates no exact-N1002K functional experiment; comparator variants make an abundance-limited mechanism plausible, but equally expressed mutants elsewhere in the protein still failed chromosome congression. The arimoclomol audit finds no target engagement or exact-variant rescue. The arrest-duration reanalysis is a checkpoint control (WT 650 min, D137R 60 min), not a drug result.
Source: Case page, question "Protein function"; records MVA-N1002K-GATE-002, MVA-ARI-007, MVA-CTRL-006 and the publications they cite
05
Hypothesis
Abundance is a starting point
Stated hypothesis of the case: stability and residual function remain unresolved; matched protein abundance must be followed by independent functional measurements. It remains proposed.
Source: Case page, 01 Summary and findings (card "N1002K / protein function")
06
Evidence
Candidates, under conditions
The 704-drug NMD screen reanalysis names montelukast as a reporter-dependent hit with no functional BUBR1 rescue. The amlexanox audit finds functional evidence in one gene and negative evidence with toxicity in another. The rapamycin reanalysis finds the BUB1B locus RNA signal 41% lower, which does not support an RNA-increase rationale. The immunotherapy audit separates tumor control from disease rescue.
Source: Records MVA-NMD-003, MVA-AMLEXANOX-010, MVA-RAP-GSE65145-001, MVA-IMMUNE-011 and the publications they cite
07
Hypothesis
Research candidates stay conditional
Stated hypothesis of the case: amlexanox and montelukast remain conditional, gentamicin plus mefloquine remains an experimental branch, and no exact-genotype pharmacological rescue is established.
Source: Case page, 01 Summary and findings (card "Research candidates")
08
Evidence
Robustness and limits (October 24, 2026)
A post-hoc exploratory computational audit, published in the research repository, re-read two earlier observations. Readthrough: the nearest set is 12 measured variant rows representing 8 unique six-base contexts, with no exact L737* context; the median paired increment stays positive under every row and context-group deletion. Rapamycin: the BUB1B-spanning RNA feature stays below the proliferative control under every specified feature, estimator and sample check. These are finite diagnostics, not confidence intervals, biological experiments or efficacy; proliferation confounding is unresolved. The candidate decision matrix is unchanged: no candidate is promoted.
Source: Case page, 05 October 24 revision: "Robustness and limits" and "Candidate decision matrix"
09
Evidence gap
What remains unresolved
Exact-variant function. L737* NMD susceptibility is predicted, not measured. N1002K stability and residual function are unresolved. Checkpoint competence and chromosome segregation have not been measured for either variant.
Source: Case page, overview: "What remains unresolved"
10
Proposed next step
The next decisive measurements
Proposed work, not performed by this project: (01) establish L737* product function and N1002K activity at matched protein abundance; (02) measure checkpoint competence and chromosome segregation separately; (03) account for viability, proliferation and completed divisions before interpreting a drug response.
Source: Case page, 06 Future validation: "The next decisive measurements"
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BioLab es el área de investigación biomédica de Stackfire Labs: casos de investigación construidos sobre evidencia abierta, reanálisis reproducibles y un registro explícito de lo que sigue sin resolverse. Organiza evidencia y propone experimentos; no realiza experimentos con pacientes ni recomienda tratamientos.
Dos variantes germinales de BUB1B en la aneuploidía variegada en mosaico plantean preguntas distintas: L737* es una pregunta de ARN y traducción; N1002K, una de estabilidad y función de la proteína. El caso registra reanálisis y auditorías de evidencia, una auditoría de robustez del 24 de octubre de 2026 y una matriz de decisión de candidatos. No hay rescate farmacológico establecido para el genotipo exacto; la validación de laboratorio sigue siendo trabajo futuro.
Un caso de investigación educativo sobre cáncer de ovario. Mantiene aparte lo que ocurrió, lo que está documentado, lo que estaba disponible en su momento, lo que se sabe hoy y lo que sigue siendo experimental. Su contenido clínico se publica solo después de una revisión y una aprobación explícita; hasta entonces las secciones muestran su estructura con estados vacíos honestos. Es una referencia educativa, no consejo médico individualizado.
Una biblioteca de investigación compartida de publicaciones guardadas como referencias, no como copias. Cada entrada enlaza a su fuente original y registra qué servicios bibliográficos públicos aportaron sus metadatos y cuándo. Los estados de lectura y las colecciones son organización bibliográfica, nunca validación científica.
El grafo conecta un caso con sus variantes, procesos, registros de evidencia, publicaciones e hipótesis. Las líneas continuas son conexiones documentadas; las discontinuas, hipótesis en revisión. Una conexión dice que una fuente o un registro vincula dos elementos: no es evidencia de causalidad ni de eficacia. Cada vista tiene también una alternativa en lista.
Una ruta de investigación es una lectura ordenada de la evidencia, paso a paso. Las hipótesis son afirmaciones en investigación con la evidencia que las informa o las limita; ninguna está marcada como validada. Los huecos de evidencia nombran lo que no se ha medido o localizado. Todos enlazan a registros y publicaciones existentes en lugar de copiarlos.
El registro auditable de los reanálisis de MVA con sus registros de ejecución y descargas, y un explorador de estructura de proteínas del modelo predicho de BUBR1. Las herramientas marcadas como planeadas aún no están construidas. Los reanálisis de datos públicos procesados y las estructuras predichas no son experimentos biológicos.
No. BioLab es contexto de investigación, no un informe diagnóstico clínico ni una recomendación de tratamiento. Los candidatos a fármaco son hipótesis de investigación con compuertas explícitas, no tratamientos probados. Las preguntas sobre la atención de una persona corresponden a su equipo clínico.
