Faculty Collaboration Database

Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2012 Mar 15;302(6):L541-54

Date

12/27/2011

Pubmed ID

22198906

Pubmed Central ID

PMC3311532

DOI

10.1152/ajplung.00282.2011

Scopus ID

2-s2.0-84858176165 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene (BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-β and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene (THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-β regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-β. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted.

Author List

Maloney JP, Stearman RS, Bull TM, Calabrese DW, Tripp-Addison ML, Wick MJ, Broeckel U, Robbins IM, Wheeler LA, Cogan JD, Loyd JE

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Binding Sites
Cell Growth Processes
Cells, Cultured
Cohort Studies
Conserved Sequence
DNA-Binding Proteins
Endothelial Cells
Familial Primary Pulmonary Hypertension
Female
Humans
Hypertension, Pulmonary
Introns
Male
Mutation, Missense
Myocytes, Smooth Muscle
Polymorphism, Genetic
Protein Binding
Pulmonary Artery
RNA Splicing
Sp1 Transcription Factor
Transcription Factors
Transforming Growth Factor beta