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Updated: Nov 21, 2025
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Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
2.8K
Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.
Roy Jung1,2, Yejin Lee1,2, Douglas Barker1,2
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Human Molecular Genetics
|January 12, 2021
Summary
Rare genetic variants in the huntingtin gene (HTT) cause Lopes-Maciel-Rodan syndrome by reducing huntingtin protein levels. This study clarifies these loss-of-function mutations and their severe impact in compound heterozygotes.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington's disease (HD) is linked to expanded CAG repeats in the HTT gene, causing toxic gain-of-function.
- Therapeutic strategies for HD often target huntingtin (HTT) suppression, but the consequences of reduced normal HTT function are not fully understood.
- Lopes-Maciel-Rodan syndrome (LOMARS) is a rare developmental disorder associated with presumed HTT loss-of-function (LoF) variants.
Purpose of the Study:
- To re-investigate rare HTT LoF variants in a family with LOMARS.
- To clarify the genetic cause and molecular mechanisms underlying LOMARS.
- To understand the effects of huntingtin deficiency.
Main Methods:
- Whole-genome sequencing of DNA from cell lines.
- Analysis of mRNA and protein expression.
- Re-annotation of HTT variants.
Main Results:
- The study corrected the annotation of two HTT variants, confirming them as the cause of LOMARS.
- Both variants were identified as hypomorphic mutations leading to reduced huntingtin levels.
- One variant caused aberrant splicing and reduced mRNA, while the other led to rapid protein turnover.
Conclusions:
- True HTT LoF variants can be transmitted by unaffected individuals.
- Compound heterozygosity for these HTT LoF variants results in severe consequences due to huntingtin deficiency.
- This provides insights into the essential role of normal huntingtin function and potential risks of HTT-lowering therapies.
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