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Updated: Nov 21, 2025
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 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.
Abstract:
Huntington's disease pathogenesis involves a genetic gain-of-function toxicity mechanism triggered by the expanded HTT CAG repeat. Current therapeutic efforts aim to suppress expression of total or mutant huntingtin, though the relationship of huntingtin's normal activities to the gain-of-function mechanism and what the effects of huntingtin-lowering might be are unclear. Here, we have re-investigated a rare family segregating two presumed HTT loss-of-function (LoF) variants associated with the developmental disorder, Lopes-Maciel-Rodan syndrome (LOMARS), using whole-genome sequencing of DNA from cell lines, in conjunction with analysis of mRNA and protein expression. Our findings correct the muddled annotation of these HTT variants, reaffirm they are the genetic cause of the LOMARS phenotype and demonstrate that each variant is a huntingtin hypomorphic mutation. The NM_002111.8: c.4469+1G>A splice donor variant results in aberrant (exon 34) splicing and severely reduced mRNA, whereas, surprisingly, the NM_002111.8: c.8157T>A NP_002102.4: Phe2719Leu missense variant results in abnormally rapid turnover of the Leu2719 huntingtin protein. Thus, although rare and subject to an as yet unknown LoF intolerance at the population level, bona fide HTT LoF variants can be transmitted by normal individuals leading to severe consequences in compound heterozygotes due to huntingtin deficiency.
Insights
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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