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- Familial Primary Pulmonary Hypertension (Gene PPH1) Is Cause...Familial Primary Pulmonary Hypertension (Gene PPH1) Is Caused by Mutations in the Bone Morphogenetic Protein Receptor–II Gene
The American Journal of Human Genetics, Volume 67, Issue 3, 1 September 2000, Pages 737-744
Zemin Deng, Jane H. Morse, Susan L. Slager, Nieves Cuervo, Keith J. Moore, George Venetos, Sergey Kalachikov, Eftihia Cayanis, Stuart G. Fischer, Robyn J. Barst, Susan E. Hodge and James A. Knowles
AbstractFamilial primary pulmonary hypertension is a rare autosomal dominant disorder that has reduced penetrance and that has been mapped to a 3-cM region on chromosome 2q33 (locus ). The phenotype is characterized by monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles. These lesions lead to elevated pulmonary-artery pressures, right-ventricular failure, and death. Although primary pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs, including phentermine-fenfluramine. We genotyped 35 multiplex families with the disorder, using 27 microsatellite markers; we constructed disease haplotypes; and we looked for evidence of haplotype sharing across families, using the program TRANSMIT. Suggestive evidence of sharing was observed with markers GGAA19e07 and D2S307, and three nearby candidate genes were examined by denaturing high-performance liquid chromatography on individuals from 19 families. One of these genes (), which encodes bone morphogenetic protein receptor type II, was found to contain five mutations that predict premature termination of the protein product and two missense mutations. These mutations were not observed in 196 control chromosomes. These findings indicate that the bone morphogenetic protein–signaling pathway is defective in patients with primary pulmonary hypertension and may implicate the pathway in the nonfamilial forms of the disease.
Abstract | Full Text | PDF (845 kb) - Identification and Functional Analysis of ZIC3 Mutations in ...Identification and Functional Analysis of ZIC3 Mutations in Heterotaxy and Related Congenital Heart Defects
The American Journal of Human Genetics, Volume 74, Issue 1, 1 January 2004, Pages 93-105
Stephanie M. Ware, Jianlan Peng, Lirong Zhu, Susan Fernbach, Suzanne Colicos, Brett Casey, Jeffrey Towbin and John W. Belmont
AbstractMutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy and have also been identified in patients with isolated congenital heart disease (CHD). To determine the relative contribution of mutations to both heterotaxy and isolated CHD, we screened the coding region of in 194 unrelated patients, including 61 patients with classic heterotaxy, 93 patients with heart defects characteristic of heterotaxy, and 11 patients with situs inversus totalis. Five novel mutations in three classic heterotaxy kindreds and two sporadic CHD cases were identified. None of these alleles was found in 97 ethnically matched control samples. On the basis of these analyses, we conclude that the phenotypic spectrum of mutations should be expanded to include affected females and CHD not typical for heterotaxy. This screening of a cohort of patients with sporadic heterotaxy indicates that mutations account for ∼1% of affected individuals. Missense and nonsense mutations were found in the highly conserved zinc finger–binding domain and in the N-terminal protein domain. Functional analysis of all currently known point mutations indicates that mutations in the putative zinc finger DNA binding domain and in the N-terminal domain result in loss of reporter gene transactivation. It is surprising that transfection studies demonstrate aberrant cytoplasmic localization resulting from mutations between amino acids 253–323 of the ZIC3 protein, indicating that the pathogenesis of a subset of mutations results at least in part from failure of appropriate nuclear localization. These results further expand the phenotypic and genotypic spectrum of mutations and provide initial mechanistic insight into their functional consequences.
Abstract | Full Text | PDF (705 kb) - Evidence That Lymphangiomyomatosis Is Caused by TSC2 Mutatio...Evidence That Lymphangiomyomatosis Is Caused by TSC2 Mutations: Chromosome 16p13 Loss of Heterozygosity in Angiomyolipomas and Lymph Nodes from Women with Lymphangiomyomatosis
The American Journal of Human Genetics, Volume 62, Issue 4, 1 April 1998, Pages 810-815
Teresa A. Smolarek, Lisa L. Wessner, Francis X. McCormack, Johanna C. Mylet, Anil G. Menon and Elizabeth Petri Henske
AbstractLymphangiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Lung transplantation is the only consistently effective therapy for LAM. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without evidence of other disease (referred to as “sporadic LAM”) or in association with tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. Renal angiomyolipomas occur in ∼50% of sporadic LAM patients and in 70% of TSC patients. Loss of heterozygosity (LOH) in the chromosomal region for the gene occurs in 60% of TSC-associated angiomyolipomas. Because of the similar pulmonary and renal manifestations of TSC and sporadic LAM, we hypothesized that LAM and TSC have a common genetic basis. We analyzed renal angiomyolipomas, from 13 women with sporadic LAM, for LOH in the regions of the (chromosome 9q34) and (chromosome 16p13) genes. LOH was detected in seven (54%) of the angiomyolipomas. We also found LOH in four lymph nodes from a woman with retroperitoneal LAM. No LOH was found. Our findings indicate that the gene may be involved in the pathogenesis of sporadic LAM. However, genetic transmission of LAM has not been reported. Women with LAM may have low-penetrance germ-line mutations, or they may be mosaic, with mutations in the lung and the kidney but not in other organs.
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Copyright © 2001 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 68, Issue 1, 92-102, 1 January 2001
doi:10.1086/316947
Report
BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension
Rajiv D Machado1, *, Michael W. Pauciulo2, *, Jennifer R. Thomson1, *, Kirk B. Lane3, Neil V. Morgan1, Lisa Wheeler3, John A. Phillips III3, John Newman3, Denise Williams1, Nazzareno Galiè4, Alessandra Manes4, Keith McNeil5, Magdi Yacoub6, Ghada Mikhail6, Paula Rogers6, Paul Corris7, Marc Humbert8, Dian Donnai9, Gunnar Martensson10, Lisbeth Tranebjaerg11, James E. Loyd3, Richard C. Trembath1, 
, 
and William C. Nichols2, ,
1 Division of Medical Genetics, Departments of Medicine and Genetics, University of Leicester, Leicester, United Kingdom
2 Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati
3 Vanderbilt University Medical Center, Nashville
4 Istituto di Cardiologia, Università di Bologna, Bologna
5 Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge
6 National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Harefield, United Kingdom
7 William Leech Centre for Lung Research, Royal Freeman Hospital, Newcastle, United Kingdom
8 Service de Pneumologie et Reanimation Respiratoire, Hôpital Antoine Beclere, Clamart, France
9 Regional Genetic Service, St. Mary’s Hospital, Manchester, United Kingdom
10 Sahlgrenska University Hospital, Division of Heart and Lung Transplant, Göteborg, Sweden
11 Department of Medical Genetics, University Hospital of Tromsö, Tromsö, Norway
Address for correspondence and reprints: Dr. Richard C. Trembath, Division of Medical Genetics, Adrian Building, University of Leicester, Leicester, England LE1 7RHDr. William C. Nichols, Division of Human Genetics, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229* The first three authors contributed equally to this article.
Abstract
Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor β (TGF-β) cell–signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.
