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Related Experiment Video

Updated: Jul 1, 2025

Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System

Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System

Published on: December 10, 2021

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT.

Maria E Bernabéu-Herrero^1,2, Dilipkumar Patel^1,2, Adrianna Bielowka^1,2

¹National Heart and Lung Institute, Imperial College London, London, United Kingdom.

|March 8, 2024

Summary

Premature termination codons (PTCs) in hereditary hemorrhagic telangiectasia (HHT) explain hemorrhage variability. PTC transcript levels rise in stressed cells, suggesting new therapeutic targets for HHT.

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Area of Science:

Genetics and Molecular Biology
Cellular Biology
Disease Mechanisms

Background:

Monogenic diseases are often studied by grouping molecular subtypes within causal genes.
Phenotypic variability in hereditary hemorrhagic telangiectasia (HHT) remains incompletely understood.
Nonsense-mediated decay (NMD) targets premature termination codon (PTC) containing transcripts.

Purpose of the Study:

To investigate the role of PTCs in HHT phenotypic variability.
To subcategorize HHT-causing variants in ENG, ACVRL1, and SMAD4 based on PTC generation.
To explore the cellular consequences of PTC persistence in HHT.

Main Methods:

Analysis of three patient cohorts with PTC-generating variants.
Culture of blood outgrowth endothelial cells (BOECs) from HHT patients.
RNA transcript analysis, gene expression profiling, pulse-chase experiments, and unsupervised hierarchical clustering.
HeLa reporter system to assess ATF4 induction and AlphaFold/AlphaMissense for protein modeling.

Main Results:

A PTC-based classification system partially explained HHT hemorrhage variability.
Low levels of PTC-containing transcripts (8-23%) persisted in HHT BOECs.
Differential gene expression in HHT BOECs clustered to generic protein terms; subtle protein maturation differences were observed, but no truncated proteins.
BOECs with higher PTC persistence showed patterns consistent with increased cellular stress.
ENG Q436X variants, but not ENG R93X, directly induced ATF4, a stress-adaptive gene regulator.
AlphaMissense predicted varying pathogenicity for readthrough substitutions depending on the specific variant.

Conclusions:

PTCs represent a distinct class of loss-of-function variants that should be differentiated.
PTC transcript levels can increase under cellular stress conditions.
Mechanisms involving readthrough proteins and stress responses present promising avenues for HHT research.