Htt
M. musculus
huntingtin
What the model saw
Gene: Htt Organism: Mus musculus Known functions: huntingtin. beta-tubulin binding. diazepam binding. dynactin binding. dynein intermediate chain binding. heat shock protein binding. identical protein binding. kinase binding. p53 binding. phosphoprotein phosphatase activity. profilin binding. protein binding. signaling receptor binding. transmembrane transporter binding.
View unredacted entry
huntingtin. beta-tubulin binding. diazepam binding. dynactin binding. dynein intermediate chain binding. heat shock protein binding. identical protein binding. kinase binding. p53 binding. phosphoprotein phosphatase activity. profilin binding. protein binding. signaling receptor binding. transmembrane transporter binding.
Solver output
Huntingtin (Htt) is a large scaffolding protein with diverse molecular interactions including dynein/dynactin binding (axonal transport), heat shock protein binding (proteostasis/chaperone network), p53 binding (apoptosis/DNA damage signaling), and profilin binding (actin cytoskeleton dynamics). In its normal wild-type form, Htt supports intracellular vesicle trafficking, autophagy scaffolding, and neuronal survival, which would be broadly pro-longevity. However, the pathological polyglutamine-expanded form causes severe proteotoxic aggregation and neurodegeneration, representing a major anti-longevity mechanism via loss of proteostasis. Since the question concerns the normal gene function in Mus musculus (not the mutant), wild-type Htt's role in supporting autophagy initiation and intracellular transport could be considered mildly pro-longevity, but its binding to p53 and kinases introduces conflicting signals. The functional annotations alone do not cleanly resolve whether normal Htt activity net promotes or opposes longevity, as its scaffolding roles span multiple hallmarks without a dominant directional effect.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted "unclear" while the ground truth is "anti_longevity." The model's reasoning acknowledges the pathological polyglutamine-expanded form as anti-longevity but then incorrectly focuses on wild-type Htt's potentially pro-longevity scaffolding roles, leading to an "unclear" conclusion. In GenAge, Htt is classified as anti_longevity for Mus musculus, which aligns with the well-known role of huntingtin mutations causing neurodegeneration and reduced lifespan. The model's mechanistic reasoning is partially correct in identifying proteostasis loss as a key mechanism, but it over-hedges by treating the wild-type vs. mutant distinction as a reason for uncertainty, when GenAge's classification is about the gene's overall influence on longevity (which is anti-longevity due to its disease-causing potential). The confidence of 0.42 reflects appropriate uncertainty but the final call is wrong.
Raw API responses
solver
{
"reasoning": "Huntingtin (Htt) is a large scaffolding protein with diverse molecular interactions including dynein/dynactin binding (axonal transport), heat shock protein binding (proteostasis/chaperone network), p53 binding (apoptosis/DNA damage signaling), and profilin binding (actin cytoskeleton dynamics). In its normal wild-type form, Htt supports intracellular vesicle trafficking, autophagy scaffolding, and neuronal survival, which would be broadly pro-longevity. However, the pathological polyglutamine-expanded form causes severe proteotoxic aggregation and neurodegeneration, representing a major anti-longevity mechanism via loss of proteostasis. Since the question concerns the normal gene function in Mus musculus (not the mutant), wild-type Htt's role in supporting autophagy initiation and intracellular transport could be considered mildly pro-longevity, but its binding to p53 and kinases introduces conflicting signals. The functional annotations alone do not cleanly resolve whether normal Htt activity net promotes or opposes longevity, as its scaffolding roles span multiple hallmarks without a dominant directional effect.",
"confidence": 0.42,
"key_pathways": [
"dynein/dynactin-mediated axonal transport",
"heat shock protein chaperone network / proteostasis",
"p53-mediated apoptosis signaling"
],
"mechanism_class": "loss_of_proteostasis",
"longevity_influence": "unclear"
}advisor
{
"notes": "The model predicted \"unclear\" while the ground truth is \"anti_longevity.\" The model's reasoning acknowledges the pathological polyglutamine-expanded form as anti-longevity but then incorrectly focuses on wild-type Htt's potentially pro-longevity scaffolding roles, leading to an \"unclear\" conclusion. In GenAge, Htt is classified as anti_longevity for Mus musculus, which aligns with the well-known role of huntingtin mutations causing neurodegeneration and reduced lifespan. The model's mechanistic reasoning is partially correct in identifying proteostasis loss as a key mechanism, but it over-hedges by treating the wild-type vs. mutant distinction as a reason for uncertainty, when GenAge's classification is about the gene's overall influence on longevity (which is anti-longevity due to its disease-causing potential). The confidence of 0.42 reflects appropriate uncertainty but the final call is wrong.",
"failure_mode": "appropriately_uncertain",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}