A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome

Abstract

Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Val665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor β. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. Distinct mutations in PDGFRB have been shown to cause infantile myofibromatosis, idiopathic basal ganglia calcification, and an overgrowth disorder with dysmorphic facies and psychosis, none of which overlaps with the clinical findings in Penttinen syndrome. We evaluated the functional consequence of this causative variant on the PDGFRB signaling pathway by transfecting mutant and wild-type cDNA into HeLa cells, and transfection showed ligand-independent constitutive signaling through STAT3 and PLCγ. Penttinen syndrome is a clinically distinct genetic condition caused by a PDGFRB gain-of-function mutation that is associated with a specific and unusual perturbation of receptor function.

NAA10 polyadenylation signal variants cause syndromic microphthalmia

“…Exome sequencing was performed on individual IV-3 and his parents at the National Institutes of Health Intramural Sequencing Center, as described 14. Identified variants in the linkage region were filtered for quality, absence in ExAC males and absence in 473 males from an in-house dataset 15 16.…”

PDGFRβ regulates craniofacial development through homodimers and functional heterodimers with PDGFRα

“…Moreover, single-nucleotide polymorphisms in the PDGFC regulatory region that repress transcriptional activity of the promoter are associated with cleft lip and palate (Choi et al 2009). In the case of PDGFRB, heterozygous missense mutations that modify amino acids in the juxtamembrane and tyrosine kinase domains cause Kosaki overgrowth syndrome (OMIM 616592) and Penttinen syndrome (OMIM 601812), respectively, both of which are characterized by facial dysmorphism and fragile skin, among other defects (Johnston et al 2015;Takenouchi et al 2015). We now show that PDGFRβ also plays a role during craniofacial development in mice and that ablation of the gene encoding this RTK in the NCC lineage can lead to cartilage, bone, and skin phenotypes in mice that emulate those found in human patients with PDGFRB mutations.…”

Insights from human genetic studies of lung and organ fibrosis

“…Other genetic defects illustrate additional dysregulated signaling pathways that lead to tissue fibrosis. For example, a missense mutation in platelet-derived growth factor receptor B (PDGFRB) leads to ligand-independent constitutive signaling of the PDGFR through STAT3 and PLCγ and causes Penttinen syndrome, an autosomal dominant disease with premature aging, digital contractures, and hyperkeratotic scars (99). Missense mutations in the gene encoding fibrillin (FBN1), clustered in the integrin-binding domain, cause stiff skin syndrome, an autosomaldominantly inherited, congenital form of scleroderma (100).…”