Identification and functional characterisation of a rare <i>MTTP</i> variant underlying hereditary non-alcoholic fatty liver disease
Bibliographic record
Abstract
Abstract Background and aims Non-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays. Results We identified a rare causal variant in MTTP , c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species. Conclusion We have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.
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 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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| 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".