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 - Funding Information:
This work was supported by the Intramural Research Program of the National Human Genome Research Institute of the NIH and by the National Institute of Neurological Disorders and Stroke grant P50 NS072187. The authors are grateful to the individuals and their families for their support and cooperation in this work. We thank Dr. Brian Brooks and Dr. Thomas Darling for their involvement and help with individual 1, Dr. Judith Martin for her involvement and help with individual 4, Dr. Heather Brandling-Bennett for her involvement and help with individual 3, Dr. Raj Kapur for his help with interpretation of the biopsy of individual 3, Dr. Maila Penttinen for contact information for individual 1, and Dr. Yujun Han for the mutation-rate-prediction analysis. We thank Drs. Pamela Schwartzberg and Harold Varmus for advice and critical evaluation of the functional data. We thank Julia Fekecs for graphic-design support. The authors thank the Exome Aggregation Consortium and the groups that provided exome-variant data for comparison. L.G.B. is an uncompensated advisor to Illumina and receives royalties from Genentech.
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
VL - 97
SP - 465
EP - 474
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
M1 - 1921
ER -