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A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome.
Am J Hum Genet. 2015 Sep 03; 97(3):465-74.AJ

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.

Authors+Show Affiliations

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.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.Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA 98195; Dermatology, Group Health Cooperative, Seattle, WA, 98112, USA.Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: lesb@mail.nih.gov.

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

26279204

Citation

Johnston, Jennifer J., et al. "A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome." American Journal of Human Genetics, vol. 97, no. 3, 2015, pp. 465-74.
Johnston JJ, Sanchez-Contreras MY, Keppler-Noreuil KM, et al. A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome. Am J Hum Genet. 2015;97(3):465-74.
Johnston, J. J., Sanchez-Contreras, M. Y., Keppler-Noreuil, K. M., Sapp, J., Crenshaw, M., Finch, N. A., Cormier-Daire, V., Rademakers, R., Sybert, V. P., & Biesecker, L. G. (2015). A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome. American Journal of Human Genetics, 97(3), 465-74. https://doi.org/10.1016/j.ajhg.2015.07.009
Johnston JJ, et al. A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome. Am J Hum Genet. 2015 Sep 3;97(3):465-74. PubMed PMID: 26279204.
* Article titles in AMA citation format should be in sentence-case
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,NiCole A, AU - Cormier-Daire,Valerie, AU - Rademakers,Rosa, AU - Sybert,Virginia P, AU - Biesecker,Leslie G, Y1 - 2015/08/13/ PY - 2015/05/15/received PY - 2015/07/21/accepted PY - 2015/8/18/entrez PY - 2015/8/19/pubmed PY - 2015/12/15/medline SP - 465 EP - 74 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 97 IS - 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. SN - 1537-6605 UR - https://www.unboundmedicine.com/medline/citation/26279204/A_Point_Mutation_in_PDGFRB_Causes_Autosomal_Dominant_Penttinen_Syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(15)00285-2 DB - PRIME DP - Unbound Medicine ER -