Publication Date
6-1-2023
Journal
Genetics in Medicine
DOI
10.1016/j.gim.2023.100833
PMID
37013900
PMCID
PMC11533975
PubMedCentral® Posted Date
11-4-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Child, Humans, Drosophila, Actins, Gain of Function Mutation, Transcription Factors, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, Drosophila, Model Organism, MRTFB, Actin, Dysmorphic Features, Intellectual Disability, Speech Apraxia
Abstract
PURPOSE: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder.
METHODS: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB.
RESULTS: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFB
CONCLUSION: The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggests these variants act as a gain of function.
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