MDGA2(chromosome 14q21.3) encodes a GPI-anchored membrane protein composed of six immunoglobulin (Ig)-like domains, a fibronectin type III domain, a MAM domain, and a C-terminal GPI anchor. Expression is restricted to the central nervous system from early embryonic development through adulthood.
Suspected pathophysiological mechanism
MDGA2 functions as a negative regulator of glutamatergic synapse development. It binds in cis to neuroligin-1 (Nlgn1) on the postsynaptic membrane, competitively interfering with the trans-synaptic neurexin-Nlgn1 interaction, thereby titrating excitatory synaptogenic drive. Loss of MDGA2 results in unrestrained Nlgn1-dependent excitatory synaptogenesis, disrupting excitatory-inhibitory synaptic balance. This mechanism was confirmed by functional studies of three representative nonsense variants in HEK293T mammalian expression systems, cultured hippocampal neurons, and heterologous synapse-formation assays: the variants lacked surface membrane trafficking and Nlgn1-binding activity, failed to suppress Nlgn1-mediated synaptogenic drive of presynaptic assembly, did not reduce excitatory synapse number, and left AMPAR-EPSC and NMDAR-EPSC amplitudes unchanged upon overexpression.
Type of mutations
Seven distinct homozygous loss-of-function variants have been identified to date in nine individuals from seven consanguineous families: nonsense, frameshift, exon deletion and splice site variants. All are predicted to result in premature termination codons, nonsense-mediated mRNA decay, or a severely truncated non-functional protein. No pathogenic missense variants have been confirmed.
Genetic testing
Diagnosis is confirmed by identification of biallelic pathogenic loss-of-function variants in MDGA2by whole exome/genome sequencing.
MDGA2