A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome

Am J Hum Genet. 2015 Sep 3;97(3):465-74. doi: 10.1016/j.ajhg.2015.07.009. Epub 2015 Aug 13.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Acro-Osteolysis / genetics*
  • Acro-Osteolysis / pathology*
  • DNA, Complementary / genetics
  • Female
  • Genes, Dominant / genetics
  • HeLa Cells
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / pathology*
  • Male
  • Mutation, Missense / genetics
  • Phosphorylation
  • Point Mutation / genetics*
  • Progeria / genetics*
  • Progeria / pathology*
  • Receptor, Platelet-Derived Growth Factor beta / genetics*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Signal Transduction / genetics*
  • Time Factors


  • DNA, Complementary
  • Receptor, Platelet-Derived Growth Factor beta

Supplementary concepts

  • Penttinen-Aula syndrome