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Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect
- Source :
- Genetics in Medicine, Genetics in Medicine, 2019, ⟨10.1038/s41436-019-0557-3⟩, Genetics in Medicine, Nature Publishing Group, 2019, ⟨10.1038/s41436-019-0557-3⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four subcomplexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13, and CDK19.We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing.All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals.Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.
- Subjects :
- Male
0301 basic medicine
MED12L
Adolescent
Autism Spectrum Disorder
Developmental Disabilities
Protein subunit
macromolecular substances
030105 genetics & heredity
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
corpus callosum
Young Adult
03 medical and health sciences
Mediator
Intellectual disability
medicine
Humans
Encoding (semiotics)
Exome
Child
Frameshift Mutation
Genetics (clinical)
Sequence Deletion
Genetics
Kinase
transcriptional defect
medicine.disease
Human genetics
030104 developmental biology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
intellectual disability
Child, Preschool
Mutation
Female
Psychology
mediator complex
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 10983600 and 15300366
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine, Genetics in Medicine, 2019, ⟨10.1038/s41436-019-0557-3⟩, Genetics in Medicine, Nature Publishing Group, 2019, ⟨10.1038/s41436-019-0557-3⟩
- Accession number :
- edsair.doi.dedup.....1aab32385ae2df8d7bdcff23e4f4eda3