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Published on: June 4, 2020
MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy
Heba Morsy1, Hyeonho Kim2, Gyubin Jang2
1Department of Neuromuscular Diseases, UCL Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Abstract:
MDGA2 encodes a membrane-associated protein that is critical for regulating glutamatergic synapse development, modulating neuroligins (Nlgns), and maintaining excitatory-inhibitory synaptic balance. While MDGA2 functions have been extensively studied in murine and cellular models, its association with human developmental disorders has yet to be established. Through exome sequencing, we identified seven distinct homozygous loss-of-function variants in MDGA2 in nine individuals from seven consanguineous families, all presenting with developmental and epileptic encephalopathy (DEE). Clinically, these individuals exhibited a consistent phenotype including infantile hypotonia, severe neurodevelopmental delay, intractable seizures, along with distinct dysmorphic features. Neuroimaging findings included delayed/incomplete myelination, early-onset brain atrophy, white-matter thinning, basal ganglia volume loss, and small hippocampi. Functional studies of three representative nonsense variants revealed impaired MDGA2 membrane trafficking, disrupted Nlgn1 interaction, and perturbed MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons. Our findings support the involvement of MDGA2 in a subtype of autosomal-recessive DEE. This not only underscores a loss-of-function pathogenic mechanism but also highlights the previously unrecognized role of MDGA2 in human synaptic development and regulation, significantly expanding our understanding of the genetic architecture of DEEs.
Insights
Loss-of-function variants in MDGA2 cause a severe neurodevelopmental disorder, developmental and epileptic encephalopathy (DEE), highlighting MDGA2's crucial role in human synaptic development and function.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- MDGA2 protein regulates glutamatergic synapse development and synaptic balance.
- Previous studies focused on MDGA2 functions in animal and cellular models.
- MDGA2's role in human developmental disorders was previously unknown.
Purpose of the Study:
- To investigate the association between MDGA2 and human developmental disorders.
- To identify the genetic basis of a specific neurodevelopmental condition.
- To elucidate the functional consequences of MDGA2 loss-of-function in humans.
Main Methods:
- Exome sequencing was used to identify genetic variants in affected individuals.
- Clinical phenotyping and neuroimaging were performed on affected individuals.
- Functional studies assessed the impact of identified MDGA2 variants on protein function in vitro.
Main Results:
- Seven distinct homozygous loss-of-function MDGA2 variants were identified in nine individuals from seven families.
- Affected individuals presented with a consistent phenotype of developmental and epileptic encephalopathy (DEE), hypotonia, severe neurodevelopmental delay, intractable seizures, and dysmorphic features.
- Functional studies confirmed impaired MDGA2 trafficking, disrupted neuroligin interaction, and perturbed synaptic function due to the identified variants.
Conclusions:
- MDGA2 loss-of-function variants are implicated in a subtype of autosomal-recessive DEE.
- This study establishes the critical role of MDGA2 in human synaptic development and regulation.
- The findings expand the understanding of the genetic causes of DEEs.
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