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Heterozygous Med13l mice recapitulate a developmental growth delay and craniofacial anomalies seen in MED13L syndrome
Anna K Leinheiser1, Timothy T Nguyen2,3, Kayla M Henry1,2
1Department of Internal Medicine, Division of Cardiovascular Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA.
Background:
Gene transcription is crucial for embryo and postnatal development and is regulated by the Mediator complex. Mediator is comprised of four submodules, including the kinase submodule (CKM). The CKM consists of MED13, MED12, CDK8, and CCNC. In mammals, there are paralogs for CKM components, including MED13L, MED12L, and CDK19. Neurological disorders have been associated with mutations in CKM genes including MED13L syndrome. MED13L syndrome is generally characterized as a haploinsufficiency of MED13L with a broad phenotypic response due in part to a wide range of de novo mutations.
Results:
We developed a Med13l heterozygous (HET) mouse model with an exon 11 deletion to evaluate whether Med13l HET mice are a viable research tool to study human phenotypes. We characterized our mouse model using growth, cardiovascular, and skeletal readouts. We observed Med13l HET mice are smaller than wildtype (WT) littermates, and over 60% of them exhibited one of two craniofacial anomalies: a pug snout with midface hypoplasia or a crooked snout. We also observed discontinuous squamosal sutures in a subset of our Med13l HETs.
Conclusions:
Med13l HET mice recapitulate MED13L syndrome phenotypes including a developmental growth delay and craniofacial anomalies. Med13l HET mice represent a novel research tool for MED13L syndrome.
Insights
A new Med13l heterozygous mouse model exhibits growth delays and craniofacial anomalies, mirroring MED13L syndrome phenotypes. This model offers a valuable tool for studying this neurological disorder.
Area of Science:
- Developmental Biology
- Genetics
- Neuroscience
Background:
- The Mediator complex regulates gene transcription essential for development.
- The kinase submodule (CKM) of Mediator, including MED13L, is implicated in neurological disorders.
- MED13L syndrome, a haploinsufficiency of MED13L, presents with diverse de novo mutations and phenotypes.
Purpose of the Study:
- To develop and characterize a Med13l heterozygous (HET) mouse model.
- To assess the utility of Med13l HET mice for studying human MED13L syndrome phenotypes.
Main Methods:
- Generation of a Med13l HET mouse model with an exon 11 deletion.
- Phenotypic characterization using growth, cardiovascular, and skeletal assessments.
Main Results:
- Med13l HET mice displayed a significant growth delay compared to wildtype littermates.
- Over 60% of Med13l HET mice exhibited craniofacial anomalies, including pug snout with midface hypoplasia or crooked snout.
- Discontinuous squamosal sutures were observed in a subset of Med13l HET mice.
Conclusions:
- Med13l HET mice successfully recapitulate key MED13L syndrome phenotypes, such as developmental growth delay and craniofacial abnormalities.
- This Med13l HET mouse model serves as a novel and valuable research tool for investigating MED13L syndrome.
