Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability
Abstract
Background: MicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions. Methods and results: In three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery. Conclusions: This study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.
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Microdeletions of miR137 have been reported in ASD, ID, and schizophrenia.
“Microdeletions of miR137 have been reported in ASD,39 ID,40 and schizophrenia.41”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [40]
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- Authors
- Willemsen, M. H., Vallès, A., Kirkels, L. A. M. H., Mastebroek, M., Olde Loohuis, N., Kos, A., Wissink-Lindhout, W. M., de Brouwer, A. P. M., Nillesen, W. M., Pfundt, R., Holder-Espinasse, M., Vallée, L., Andrieux, J., Coppens-Hofman, M. C., Rensen, H., Hamel, B. C. J., van Bokhoven, H., Aschrafi, A., & Kleefstra, T.
- Affiliations
- Radboud University Medical Center (NL)
- Radboud University Nijmegen (NL)
- Pluryn (NL)
- Centre Hospitalier Universitaire de Lille (FR)
- Corresponding author
- Kleefstra, Tjitske
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2011-10-15
- Volume
- 48
- Issue
- 12
- Pages
- 810-818
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2137932411
- Cited by
- 202
- References
- 51
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 15 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 5 · 2019: 15 · 2018: 40 · 2017: 11 · 2016: 14 · 2015: 14 · 2014: 26 · 2013: 19 · 2012: 13
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- intellectual disability, microRNA-137, dihydropyrimidine dehydrogenase, dihydropyrimidine dehydrogenase deficiency, dosage effect, MITF, EZH2, KLF4, synaptic protein synthesis, hippocampal neurons, cortical neurons, microRNA expression
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Kruppel-Like Factor 4, Adolescent, Adult, Animals, Chromosome Deletion, Chromosomes, Human, Pair 1, DNA-Binding Proteins, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Intellectual Disability, Neurons, Phenotype, Transcription Factors, Transfection, Gene Dosage, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, MicroRNAs, Dihydrouracil Dehydrogenase (NADP), Rats, Microphthalmia-Associated Transcription Factor, Kruppel-Like Transcription Factors, DNA Copy Number Variations, Primary Cell Culture, Polycomb Repressive Complex 2
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