ArticleHuman molecular genetics2021
Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 35 citations in OpenAlex.
- High-affinity, structure-validated and selective macrocyclic peptide tools for chemical biology studies of Huntingtin.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- High-Affinity, Structure-Validated and Selective Macrocyclic Peptide Tools for Chemical Biology Studies of Huntingtin.bioRxiv : the preprint server for biology · 2025Article
- HTT loss-of-function contributes to RNA deregulation in developing Huntington's disease neurons.Cell & bioscience · 2025Article
- Genomic characterization of Huntington's disease genetic modifiers informs drug target tractability.Brain communications · 2025Article
- Huntingtin is an RNA binding protein and participates inScience advances · 2024Article
- Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.Journal of Huntington's disease · 2024Article
- Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration.Brain : a journal of neurology · 2023Article
- Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40.Structure (London, England : 1993) · 2023Article
- Computational insights into missense mutations in HTT gene causing Huntington's disease and its interactome networks.Irish journal of medical science · 2023Article
- Article
- Recent approaches on Huntington's disease (Review).Biomedical reports · 2023Review
- Description of the First Registered Case of Lopes-Maciel-Rodan Syndrome in Russia.International journal of molecular sciences · 2022Review
- PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease.Molecular therapy. Methods & clinical development · 2022Article
- A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function.JCI insight · 2022Article
- Common huntingtin-related genetic variation is associated with neurobiological and aging traits in humans.Cell death discovery · 2022Article
- Huntington's disease: nearly four decades of human molecular genetics.Human molecular genetics · 2021Review
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Authors and funding
20 authors at 4 institutions in 1 country.
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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.
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