title: 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.
  
  
  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.
authors: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Marjolein H
authors: MH
authors: Willemsen
authors: Astrid
authors: A
authors: Vallès
authors: Laurens A M H
authors: LA
authors: Kirkels
authors: Mathilde
authors: M
authors: Mastebroek
authors: Nikkie
authors: N
authors: Olde Loohuis
authors: Aron
authors: A
authors: Kos
authors: Willemijn M
authors: WM
authors: Wissink-Lindhout
authors: Arjan P M
authors: AP
authors: de Brouwer
authors: Willy M
authors: WM
authors: Nillesen
authors: Rolph
authors: R
authors: Pfundt
authors: Muriel
authors: M
authors: Holder-Espinasse
authors: Louis
authors: L
authors: Vallée
authors: Joris
authors: J
authors: Andrieux
authors: Marjolein C
authors: MC
authors: Coppens-Hofman
authors: Hanneke
authors: H
authors: Rensen
authors: Ben C J
authors: BC
authors: Hamel
authors: Hans
authors: H
authors: van Bokhoven
authors: Armaz
authors: A
authors: Aschrafi
authors: Tjitske
authors: T
authors: Kleefstra
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D063151:Polycomb Repressive Complex 2; D020641:Polymorphism, Single Nucleotide; D061251:Primary Cell Culture; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C545567:MIRN137 microRNA, human; C497234:MITF protein, human; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors; D042943:Dihydrouracil Dehydrogenase (NADP); C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2