J Med Genet 48:810-818 doi:10.1136/jmedgenet-2011-100294
  • Copy-number variation
  • Original article

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

  1. Tjitske Kleefstra1
  1. 1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Department of Molecular Animal Physiology, Radboud University Nijmegen, Nijmegen, The Netherlands
  3. 3Department of Neurocognition, Maastricht University, Maastricht, The Netherlands
  4. 4Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  5. 5Pluryn, Support for People with Disabilities, Oosterbeek, The Netherlands
  6. 6Service de Génétique Clinique, CHRU, Lille, France
  7. 7Service de neuropédiatrie, CHRU, Lille, France
  8. 8Plateforme de Génomique, CHRU, Lille, France
  9. 9Department of Medical Psychology, Radboud University Nijmegen, Nijmegen, The Netherlands
  1. Correspondence to Dr Tjitske Kleefstra, RUNMC, 849 Department of Human Genetics, PO Box 9101, 6500 HB Nijmegen, The Netherlands; t.kleefstra{at}
  1. Contributors I declare that all contributing authors included on this paper fulfil the criteria of authorship and are all in agreement with the publication.

  • Received 28 June 2011
  • Revised 16 September 2011
  • Accepted 28 September 2011
  • Published Online First 15 October 2011


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.


  • AA and TK contributed equally to this work.

  • Funding This work was supported by grants from the Consortium ‘Stronger on your own feet’ (to TK, MCCH, MHW); the Donders Center for Neuroscience fellowship award of the Radboud University Nijmegen Medical Centre (to AA); the FP7-Marie Curie International Reintegartion Grant (to AA); GENCODYS, an EU FP7 large-scale integrating project grant (grant number 241995) and ZonMW (clinical fellowship, grant number 90700365 to TK).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was approved by the local ethical committee of the Radboud University Nijmegen, The Netherlands.

  • Provenance and peer review Not commissioned; externally peer reviewed.