HGNC Approved Gene Symbol: PLXND1
Cytogenetic location: 3q22.1 Genomic coordinates (GRCh38): 3:129,555,214-129,606,676 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q22.1 | Congenital heart defects, multiple types, 9 | 620294 | Autosomal recessive | 3 |
The PLXND1 gene encodes a 521-residue protein that is a member of the plexin family of proteins. Plexins bind to semaphorins, a large family of extracellular secreted and membrane proteins. PLXND1 is highly expressed in the vascular system (summary by Tomas-Roca et al., 2015).
Tamagnone et al. (1999) identified the cDNA sequence of a novel member of the plexin gene family and named the gene plexin D1.
By genomic sequence analysis, Tamagnone et al. (1999) mapped the PLXND1 gene to chromosome 3.
Stumpf (2020) mapped the PLXND1 gene to chromosome 3q22.1 based on an alignment of the PLXND1 sequence (GenBank BC150280) with the genomic sequence (GRCh38).
By in situ hybridization of mouse embryos, Gitler et al. (2004) found that Plxnd1 was expressed by embryonic vascular endothelial cells. Expression was robust in endocardium, intersomitic vessels, pulmonary vasculature, aorta, and pharyngeal arch arteries. In adult mice, Plxnd1 was expressed in heart, brain, lung, kidney, and testis, consistent with broad expression in endothelial cells. Human vascular endothelial cells also expressed PLXND1. Gitler et al. (2004) demonstrated that mouse Plxnd1 heterodimerized with Npn1 (602069) to form a functional Sema3C (602645) receptor. Binding of Sema3A (603961) and Sema3C to COS cells expressing Npn1 was enhanced by cotransfection of Plxnd1. Plxnd1 also enhanced binding of Sema3C to Npn2 (602070).
Gu et al. (2005) found that signaling by semaphorin-3E (SEMA3E; 608166) and its receptor plexin-D1 controls endothelial cell positioning and the patterning of developing vasculature in the mouse. Sema3e is highly expressed in developing somites, where it acts as a repulsive cue for plexin-D1-expressing endothelial cells of adjacent intersomitic vessels. Sema3e-plexin-D1 signaling did not require neuropilins (see 602069), which had been presumed to be obligate Sema3 coreceptors. Moreover, genetic ablation of Sema3e or plexin-D1 but not neuropilin-mediated Sema3 signaling disrupted vascular patterning. Gu et al. (2005) concluded that their results reveal an unexpected semaphorin signaling pathway and define a mechanism for controlling vascular patterning.
Pecho-Vrieseling et al. (2009) showed that a recognition system of a specific sensory motor connection involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 by proprioceptive sensory neurons, is a critical determinant of synaptic specificity in sensory motor circuits in mice. Changing the profile of Sema3e-Plxnd1 signaling in sensory or motor neurons results in functional and anatomic rewiring of monosynaptic connections, but does not alter motor pool specificity. Pecho-Vrieseling et al. (2009) concluded that patterns of monosynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signaling.
By immunofluorescent labeling of sagittal sections of mouse heads at embryonic day (E) 12.5, Cariboni et al. (2015) observed abundant expression of Plxnd1, with localization to nasal axons and blood vessels as well as to the olfactory epithelium (OE) and vomeronasal organ (VNO). However, most GnRH (152760)-positive cells (corresponding to GnRH neurons) within the OE and VNO or elsewhere in the nose appeared only faintly positive or were negative for Plxnd1. Examination of E14.5 mouse heads showed a similar pattern of faint-to-negative Plxnd1 expression for GnRH neurons migrating in the nose, whereas GnRH neurons that had entered the forebrain began to express Plxnd1. In addition, GnRH neurons in the medial preoptic area, where most hypothalamic GnRH neurons eventually reside, expressed Plxnd1 strongly on both their cell bodies and axons. Cariboni et al. (2015) suggested that Sema3e signaling through Plxnd1 is a requirement for developing GnRH neurons after they have entered the brain.
Mehta et al. (2020) showed that PLXND1 has a role in mechanosensation and mechanically induced disease pathogenesis in endothelial cells. PLXND1 is required for the response of endothelial cells to shear stress in vitro and in vivo and regulates the site-specific distribution of atherosclerotic lesions. In endothelial cells, PLXND1 is a direct force sensor and forms a mechanocomplex with neuropilin-1 (NRP1; 602069) and VEGFR2 (191306) that is necessary and sufficient for conferring mechanosensitivity upstream of the junctional complex and integrins. PLXND1 achieves its binary functions as either a ligand or a force receptor by adopting 2 distinct molecular conformations. Mehta et al. (2020) concluded that their results established a previously undescribed mechanosensor in endothelial cells that regulates cardiovascular pathophysiology, and provided a mechanism by which a single receptor can exhibit a binary biochemical nature.
Multiple Types of Congenital Heart Defects 9
In a consanguineous Iranian Jewish family in which 3 sisters had isolated truncus arteriosus and 1 had tetralogy of Fallot with pulmonary atresia and multiple collaterals from the aortic arch and descending aorta to the lung fields (CHTD9; 620294), Ta-Shma et al. (2013) identified homozygosity for a missense mutation in the PLXND1 gene (R1299C; 604282.0001) in the 1 surviving affected sister. The unaffected parents and 5 unaffected sibs were heterozygous for the mutation, which was not found in 60 Iranian Jewish controls or in public variant databases.
In 10 patients from 5 unrelated families with common arterial trunk and/or other cardiovascular defects, Guimier et al. (2023) identified homozygosity or compound heterozygosity for mutations in the PLXND1 gene (see, e.g., 604282.0002-604282.0005). The mutations segregated with disease in each family and were not found in the gnomAD database, except for 1 at very low minor allele frequency, only in heterozygosity.
Associations Pending Confirmation
--Moebius Syndrome
In a patient diagnosed with Moebius syndrome (157900), Tomas-Roca et al. (2015) identified a de novo heterozygous missense variant (c.5685C-A, N1895K; NM_015103) in the PLXND1 gene. The mutation was found by trio whole-exome sequencing and confirmed by Sanger sequencing. Sanger sequencing of candidate genes, including PLXND1, in 103 patients diagnosed with Moebius syndrome identified 1 additional patient with a de novo heterozygous missense variant (c.4454-4455GC-CA, R1485P) and 1 patient with a silent variant (c.3018C-T, L1006L). Functional studies of the variants and studies of patient cells were not performed.
In a Pakistani boy who exhibited features of both Moebius and Poland (173800) syndromes, Glass et al. (2022) identified heterozygosity for a missense mutation (c.2890G-A, V964M; rs553781761) within the amino-terminal IPT domain in the PLXND1 gene. The variant was inherited from his unaffected mother, and was present at low minor allele frequency in the gnomAD database (8.38 x 10(-5)). The authors stated that their report provided further circumstantial evidence of a causal link, but suggested that either penetrance varies widely between cases, or that unidentified variables contribute to the phenotype.
--Anomalous Pulmonary Venous Return
Zhou et al. (2022) performed whole-exome sequencing in 144 Chinese patients with anomalous pulmonary venous return (APVR; see 106700) and 1,636 healthy Chinese controls and observed enrichment of potentially deleterious variants in genes highly expressed in the human heart at the critical time point for development of pulmonary veins draining into the left atrium. The authors noted that PLXND1 represented a strong candidate gene, and validated the finding in an independent cohort of 82 case-control pairs. The 8 patients carrying heterozygous PLXND1 variants had a remarkably similar phenotype, in that the anomalous drainage of pulmonary veins occurred on the right side with incorrect connections to the right atrium in all patients, and all had type II atrial septal defects. Parental segregation was not reported for 6 patients; 1 variant was reported as de novo, and in the remaining case, the variant was inherited from an unaffected father. The authors suggested that PLXND1 represented a potentially important APVR-associated gene.
Gitler et al. (2004) found that Plxnd1 knockout mouse pups became cyanotic shortly after birth and succumbed within 24 hours. All newborn homozygotes had structural cardiovascular defects involving the outflow tract of the heart and derivatives of the aortic arch arteries. In Plxnd1 knockout embryos, the right and left pulmonary arteries arose from the persistent truncus arteriosus, indicating a failure of outflow tract septation. Cardiac neural crest migration was unaffected in mutant mice.
Torres-Vazquez et al. (2004) identified a mutation in the Plxnd1 gene in the zebrafish vascular patterning mutant 'out of bounds.' They showed that zebrafish Plxnd1 and semaphorin signals were required for proper blood vessel pathfinding.
In sagittal sections of E14.5 heads from Plxnd1-null mice, Cariboni et al. (2015) performed immunohistochemical staining for GnRH (152760) followed by quantification and observed a significant reduction in the number of GnRH neurons in mutant compared to wildtype mouse heads. Further analysis demonstrated that the number of GnRH-positive cells was similar in the nose of both genotypes, whereas their numbers were significantly reduced in the forebrain of Plxnd1-null mice compared with wildtype. Examination of the medial preoptic area (MPOA) of Plxnd1-null mice and their littermates during late embryogenesis showed that many GnRH neurons were present in the wildtype MPOA at E17.5, whereas GnRH neurons were sparse in littermate mutants and residual neurons appeared collapsed; heterozygous mice had a normal number of GnRH neurons. Labeling for GnRH and the apoptosis marker activated caspase-3 in coronal sections through the MPOA showed that GnRH neurons were sparse and apoptotic cells prominent in the mutant MPOA; quantification confirmed a significant increase in the number of apoptotic cells in the mutant MPOA compared to wildtype. Cariboni et al. (2015) concluded that loss of PLXND1 signaling compromises GnRH neuron survival in the developing brain. In addition, the median eminence of neuron-specific Plxnd1-null adult male mice was poorly innervated by GnRH-positive axons compared to wildtype males, and the testes of adult male mice lacking neuronal Plxnd1 were smaller than those of wildtype littermates.
Tomas-Roca et al. (2015) found that the embryonic brains of Plxnd1-null mice showed hypoplasia of the corpus callosum, anterior commissure, and fasciculus retroflexus, all of which are bundles of neural fibers that connect brain areas. Homozygous-null mice had a significant reduction in the number of motoneurons in the facial branchiomotor nucleus compared to wildtype. Immunohistochemical studies showed that both homozygous-null and heterozygous-null Plxnd1 mice had impaired motoneuron migration during embryonic brain development.
Using CRISPR/Cas9 technology, Zhou et al. (2022) generated homozygous Plxnd1-knockout mice and examined cardiac morphology at embryonic day (E) 16.5. Nearly all had persistent truncus arteriosus and ventricular septal defect, and all showed severe noncompaction of the ventricular myocardium. Incomplete atrial septal closure was observed in about one-third of the homozygous mutants; atrial and ventricular septal defects as well as noncompaction were also observed in heterozygotes, but at lower penetrance. In addition, in approximately one-third of homozygous mutants, the coronary sinuses incorrectly entered the left atrium, and the pulmonary vein opening was located between the coronary sinus and the atrial septum. Evaluation of pulmonary vascular development at E18.5 revealed severely thickened saccular septa between neighboring saccules with increased capillary density in homozygotes compared with wildtype and heterozygous mice. Misaligned pulmonary venules, presenting in the center of the lung lobule surrounding the bronchoarterial bundles instead of in their normal location in the periphery of the lobule within the interlobular septa, were also observed. In a scratch wound assay, isolated pulmonary vascular endothelial cells from the homozygous mutant mice migrated more rapidly and moved significantly longer total distances than wildtype cells, and a vessel-like formation assay showed that the Plxnd1-null cells significantly enhanced vessel-like formation at 3 hours compared to wildtype controls. The authors concluded that Plxnd1 deficiency disturbs the development of cardiac and pulmonary blood vessels.
In a consanguineous Iranian Jewish family, previously reported by Rein et al. (1990) and Rein and Sheffer (1994), in which 3 sisters had isolated truncus arteriosus and 1 had tetralogy of Fallot with pulmonary atresia and multiple collaterals from the aortic arch and descending aorta to the lung fields (CHTD9; 620294), Ta-Shma et al. (2013) performed exome sequencing in the 1 surviving sister and identified homozygosity for a chr3:129286619C-T transition in exon 21 of the PLXND1 gene, resulting in an arg1299-to-cys (R1299C) substitution at a highly conserved residue. The unaffected first-cousin parents and 5 unaffected sibs were heterozygous for the mutation, which was not found in 60 Iranian Jewish controls or in the Exome Variant Server or dbSNP (build 137) databases. The mutation also was not detected in a male first cousin once removed with transposition of the great arteries; DNA was not available from a deceased female second cousin who had double-outlet right ventricle with unbalanced complete atrioventricular canal defect, hypoplastic left ventricle, and septal defects, or from her parents.
In 3 sibs of North African origin (family F1) with common arterial trunk and variable other cardiac anomalies (CHTD9; 620294), Guimier et al. (2023) identified homozygosity for a c.5323A-T transversion (c.5323A-T, NM_015103.2) in the PLXND1 gene, resulting in an ile1775-to-phe (I1775F) substitution within the GAP domain. Their unaffected first-cousin parents and an unaffected sister and brother were heterozygous for the mutation; another unaffected sister did not carry the variant, which was not found in the gnomAD database.
In a brother and sister of African American, Caucasian, and Hispanic ancestry (family F2), who had common arterial trunk and bicuspid or quadricuspid aortic valve, as well as right aortic arch in the sister (CHDT9; 620294), Guimier et al. (2023) identified compound heterozygosity for mutations in the PLXND1 gene: a c.2733C-G transversion (c.2733C-G, NM_015103.2), resulting in an ile911-to-met (I911M) substitution within the first IPT domain; and a 2-bp deletion (c.880_881delCA; 604282.0003), causing a frameshift predicted to result in a premature termination codon (Gln294ValfsTer232) within the Sema domain. Their unaffected mother and an unaffected brother were heterozygous for the 2-bp deletion; their father was not tested. The I911M substitution was not found in the gnomAD database, whereas the 2-bp deletion was present at very low minor allele frequency.
For discussion of the 2-bp deletion (c.880_881delCA, NM_015103.2) in the PLXND1 gene, causing a frameshift predicted to result in a premature termination codon (Gln294ValfsTer232), that was found in compound heterozygous state in a brother and sister with multiple types of congenital heart defects (CHTD9; 620294) by Guimier et al. (2023), see 604282.0002.
In 2 fetuses from a Gambian family (family F3), one with ventricular hypoplasia and the other with a single ventricle and single outlet artery (CHTD9; 620294), Guimier et al. (2023) identified homozygosity for a c.652A-T transversion (c.652A-T, NM_015103.2) in the PLXND1 gene, resulting in a ser218-to-cys (S218C) substitution within the Sema domain. The unaffected parents were heterozygous for the substitution, which was not found in the gnomAD database.
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Gu, C., Yoshida, Y., Livet, J., Reimert, D. V., Mann, F., Merte, J., Henderson, C. E., Jessell, T. M., Kolodkin, A. L., Ginty, D. D. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307: 265-268, 2005. [PubMed: 15550623] [Full Text: https://doi.org/10.1126/science.1105416]
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Torres-Vazquez, J., Gitler, A. D., Fraser, S. D., Berk, J. D., Pham, V. N., Fishman, M. C., Childs, S., Epstein, J. A., Weinstein, B. M. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev. Cell 7: 117-123, 2004. [PubMed: 15239959] [Full Text: https://doi.org/10.1016/j.devcel.2004.06.008]
Zhou, W.-Z., Zeng, Z., Shen, H., Chen, W., Li, T., Ma, B., Sun, Y., Yang, F., Zhang, Y., Li, W., Han, B., Liu, X., Yuan, M., Zhang, G., Yang, Y., Liu, X., Pang, K.-J., Li, S.-J., Zhou, Z. Association of PLXND1 with a novel subtype of anomalous pulmonary venous return. Hum. Molec. Genet. 31: 1443-1452, 2022. [PubMed: 34791216] [Full Text: https://doi.org/10.1093/hmg/ddab331]