Abstract
PurposeTo investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. MethodsWe assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype–phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. ResultsShared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. ConclusionWe propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Highlights
Plexins are a large family of cell surface receptors for the axon guidance molecules semaphorins
Three studies reported monoallelic de novo variants in PLXNA1 to be associated with infantile-onset epilepsy, intellectual disability with autism spectrum disorder (ASD), epileptic encephalopathy, or schizophrenia in the respective patients.[16,17,18,19]
Biallelic and monoallelic PLXNA1 variants In four families, we identified seven patients with biallelic variants in PLXNA1 segregating with the disease (Fig. 1a)
Summary
Plexins are a large family of cell surface receptors for the axon guidance molecules semaphorins. Plexin-A1 and its co-receptor Neuropilin-1 (NRP1) bind different classes of semaphorins.[1,2,3,4] The Plexin cytoplasmic domain contains two segments (C1 and C2) that have sequence similarity to GTPase-activating protein (GAP) and form a functional GAP domain.[5] Before semaphorin binding, plexin is an inactive monomer or dimer in which the RapGAP activity is autoinhibited.[6] Semaphorin-induced dimerization of the plexin extracellular region promotes formation of the activating dimer of the cytoplasmic region, which converts the GAP domain to the active state through an allosteric mechanism.[6,7,8] The PlexinA1 GAP domains show dual specificity for Rac and Rap GTPases.[9] Plxna[1] null mice exhibit different axonal abnormalities (e.g., abnormal proprioceptive neuronal and oligodendrocyte morphology, slight defasciculation of optic chiasm, aberrant crossing of commissural axons, agenesis of corpus callosum [CC], and defects in the olfactory and neuroendocrine reproductive systems).[10,11,12,13] Plxna[1] null mice exhibit neuronal abnormalities with rarefied interneurons in developing cortex and a decreased cortical thickness.[14] Recently, van der Klaauw et al implicated rare monoallelic variants in plexins and semaphorins in the expression of severe obesity.[15] They found 40 rare variants in 13 plexin and semaphorin genes. Three studies reported monoallelic de novo variants in PLXNA1 to be associated with infantile-onset epilepsy, intellectual disability with autism spectrum disorder (ASD), epileptic encephalopathy, or schizophrenia in the respective patients.[16,17,18,19]
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