TY - JOUR
T1 - A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome
AU - Johnston, Jennifer J.
AU - Sanchez-Contreras, Monica Y.
AU - Keppler-Noreuil, Kim M.
AU - Sapp, Julie
AU - Crenshaw, Molly
AU - Finch, Ni Cole A.
AU - Cormier-Daire, Valerie
AU - Rademakers, Rosa
AU - Sybert, Virginia P.
AU - Biesecker, Leslie G.
N1 - Publisher Copyright:
© 2015 The American Society of Human Genetics.
PY - 2015/9/3
Y1 - 2015/9/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2015.07.009
DO - 10.1016/j.ajhg.2015.07.009
M3 - Article
C2 - 26279204
AN - SCOPUS:84941023547
SN - 0002-9297
VL - 97
SP - 465
EP - 474
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
M1 - 1921
ER -