A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome.
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.
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Jennifer J
JJ
Johnston
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Monica Y
MY
Sanchez-Contreras
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Kim M
KM
Keppler-Noreuil
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Julie
J
Sapp
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
Molly
M
Crenshaw
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
NiCole A
NA
Finch
INSERM UMR1163, Département de Génétique, Université Paris Descartes, Sorbonne Paris Cité and Institut Imagine, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris 75006, France.
Valerie
V
Cormier-Daire
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Rosa
R
Rademakers
Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA 98195; Dermatology, Group Health Cooperative, Seattle, WA, 98112, USA.
Virginia P
VP
Sybert
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: lesb@mail.nih.gov.
Leslie G
LG
Biesecker
D030981:Acro-Osteolysis / Q000235:genetics* / Q000473:pathology*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics*; D011371:Progeria / Q000235:genetics* / Q000473:pathology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors
D018076:DNA, Complementary; D020797:Receptor, Platelet-Derived Growth Factor beta