ArticleMolecular genetics & genomic medicine2019
Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.
Article in Molecular genetics & genomic medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Global Co-regulatory Cross Talk Between mMolecular neurobiology · 2025Article
- Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Article
- Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes.American journal of medical genetics. Part A · 2023Article
- Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction iniScience · 2022Article
- Review
- De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Somatic andFrontiers in cell and developmental biology · 2021Article
- Mutations in Mediator Complex GenesMolecular syndromology · 2020Article
- Article
- Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.Molecular genetics & genomic medicine · 2019Article
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Authors and funding
16 authors at 10 institutions in 4 countries.
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Abstract
backgroundMutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood.
methodsQuantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations.
resultsThree newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain.
conclusionsThese results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.
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