Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability

M.H. Willemsen, A. Valles Sanchez, L.A.M.H. Kirkels, M. Mastebroek, N. Olde Loohuis, A. Kos, W.M. Wissink-Lindhout, A.P.M. Brouwer, W.M. Nillesen, R. Pfundt, M. Holder-Espinasse, L. Vallée, J. Andrieux, M.C. Coppens-Hofman, H. Rensen, B.C.J. Hamel, H. van Bokhoven, A. Aschrafi, T. Kleefstra*

*Corresponding author for this work

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117 Citations (Web of Science)


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.
Original languageEnglish
Pages (from-to)810-818
JournalJournal of Medical Genetics
Issue number12
Publication statusPublished - 1 Jan 2011

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