PLXNA2 identified as a candidate gene by genome-wide association analysis for mandibular prognathism in human chondrocytes

Abstract

Abstract. In a previous genome-wide association study, plexin A2 (PLXNA2) was suggested as one of the candidate genes for mandibular prognathism. PLXNA2 encodes plexin A2, a member of the plexin-A family of semaphorin co-receptors. Semaphorin 3A (sema3A) exerts an osteoprotective effect. However, to the best of our knowledge, there have been no previous studies examining the role of sema3A or plexin A2 on human chondrocytes. The objectives of the present study were to examine the function of sema3A and its receptor, plexin A2, in human chondrocytes. Normal human chondrocytes were cultured in media with either a high (100 ng/ml) or a low (1 ng/ml) concentration of sema3A, or without sema3A as a control. Cells and extracellular matrices were assayed for concentrations of protein and parathyroid hormone-related peptide receptor 1 (PTH-R1) using a bicinchoninic acid assay and an enzyme immunoassay, respectively. At culture day 7, the high and low concentrations of exogenous sema3A significantly increased the protein content compared with the control (P=0.0008 and 0.00002, respectively). At culture day 14, a high concentration of exogenous sema3A significantly increased the protein content and decreased the concentration of PTH-R1 compared with the control (P=0.002). The present study revealed novel results that exogenous sema3A suppresses the expression of PTH-R1 in human proliferative chondrocytes and suggested that sema3A may affect human chondrocytes via its receptor, plexin A2.

PLXNA2 as a candidate gene in patients with intellectual disability

“…Plexin A2 is also expressed in human chondrocytes where it is believed to bind with semaphorin 3A, a secreted protein that is expressed by osteoblasts, and induce osteoblastic differentiation, the acceleration of cell growth, and the accumulation of extracellular matrices of chondrocytes (Gomez et al, 2005; Hayashi et al, 2012; Kajii et al, 2018). Genome‐wide association study performed on 240 Japanese patients with mandibular prognathism suggested PLXNA2 as a susceptibility locus (Kajii et al, 2018). Possibly reinforcing the role of PLXNA2 in jaw malformations, our study describes an obtuse mandibular angle and a mild overbite shared by the index in Family 1 and the index of Family 2.…”

Missense polymorphisms potentially involved in mandibular prognathism

“… 30 The interaction of two proteins may suppress the expression of parathyroid hormone-related peptide receptor 1 (PTH-R1) in human proliferative chondrocytes. 31 This is significant because the parathyroid hormone-related protein and its receptor PTH-R1 play a crucial role in regulating chondrocyte proliferation, differentiation, and apoptosis. 32 As most chondrocytes in the mandibular condylar cartilage undergo programmed death, the cartilage matrix is replaced by bone through endochondral ossification, ultimately forming the mandibular condyle.…”

Syringohydromyelia in Dogs: The Genomic Component Underlying a Complex Neurological Disease

“…A missense mutation in BMP3 has been identified as a major contributor to brachycephaly [ 31 ], and a repeat expansion of the RUNX2 gene has been correlated with snout dorsiflexion and midface length in dogs [ 29 ]. Recently, Kajii et al [ 40 ] suggested that PLXNA2 may be a candidate gene for mandibular prognathism since its mutation can delay the early termination of condylar growth. According to this, association of PLXNA2 with SHM could be explained by affecting CCJ and/or vertebral column bone formation, disturbing CSF flow and consequently inducing the formation of syringes.…”