A Physical and Transcript Map Based upon Refinement of the Critical Interval for PPH1, a Gene for Familial Primary Pulmonary Hypertension

doi:10.1006/geno.2000.6291

Genomics

Volume 68, Issue 2, 1 September 2000, Pages 220-228

https://doi.org/10.1006/geno.2000.6291 Get rights and content

Abstract

Primary pulmonary hypertension (PPH), an often fatal disorder, is characterized by sustained elevation of pulmonary artery pressure of unknown cause. In its familial form (FPPH), the disorder segregates as an autosomal dominant and displays markedly reduced penetrance. A gene for FPPH was previously localized to a 25-cM interval on the long arm of chromosome 2 (2q31–q33). We now report a complete yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAC)/P1 artificial chromosome contig (PAC), assembled by STS content mapping, across a newly identified minimum nonrecombinant interval containing the gene designated PPH1. The physical map has served to establish polymorphic marker order unequivocally, enabling the establishment of detailed haplotypes for the region. Together with the identification of novel recombination events in affected individuals from six newly ascertained kindreds, these data have allowed the significant reduction of the minimum PPH1 critical interval to a 4.8-cM region. The region, flanked by the polymorphic markers D2S115 (centromeric) and D2S1384 (telomeric), corresponds to a minimum physical distance of 5.8 Mb at 2q33. Numerous expressed sequence tags and known genes were placed on the YAC/BAC contig spanning the PPH1 gene critical region.

References (42)

T. Fernandes-Alnemri et al.
CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme
J. Biol. Chem.
(1994)
S. Hadano et al.
A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33–q34
Genomics
(1999)
J. Hanes et al.
Characterization by cDNA cloning of two new human protein kinases. Evidence by sequence comparison of a new family of mammalian protein kinases
J. Mol. Biol.
(1994)
K.W. Johnson et al.
Molecular cloning of a novel human cdc2/CDC28-like protein kinase
J. Biol. Chem.
(1991)
M. Kawabata et al.
Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor
J. Biol. Chem.
(1995)
W.C. Nichols et al.
Mutations in the ER–Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII
Cell
(1998)
C.W. Oakley
Primary pulmonary hypertension. Case series from the United Kingdom
Chest
(1994)
Z. Shen et al.
UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins
Genomics
(1996)
K. Takahara et al.
Mouse and human homologues of the yeast origin of replication recognition complex subunit ORC2 and chromosomal localization of the cognate human gene ORC2L
Genomics
(1996)
T. Tamura et al.
Molecular cloning and sequence analysis of cDNAs for five major subunits of human proteasomes (multi-catalytic proteinase complexes)
Biochim. Biophys. Acta
(1991)

J. Wang et al.

Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II

Cell

(1999)

R. Berger et al.

Analysis of aldehyde oxidase and xanthine dehydrogenase/oxidase as possible candidate genes for autosomal recessive familial amyotrophic lateral sclerosis

Somat. Cell Motil. Gene

(1995)

M.D. Botney et al.

Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta

Am. J. Pathol.

(1994)

S.C. Chandrasekharappa et al.

Analysis of yeast artificial chromosome clones

R.W.J. Cottingham et al.

Faster sequential genetic linkage computations

Am. Hum. Genet.

(1993)

B. Coyle et al.

Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4

Nat. Genet.

(1996)

Z. Dai et al.

Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity

Genes Dev.

(1995)

G.E. D'Alonzo et al.

Survival in patients with primary pulmonary hypertension. Results from a national prospective registry

Ann. Intern. Med.

(1991)

P. Dariavach et al.

Human Ig superfamily CTLA-4 gene: Chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains

Eur. J. Immunol.

(1988)

P. Deloukas et al.

A physical map of 30,000 human genes

Science

(1998)

Cited by (24)

Molecular mechanisms of pulmonary arterial hypertension: Role of mutations in the bone morphogenetic protein type II receptor
2008, Chest
Pulmonary arterial hypertension (PAH) is characterized by abnormal remodeling of small, peripheral resistance vessels in the lung involving proliferation and migration of vascular smooth muscle, endothelial cell and fibroblasts. The increase in pulmonary vascular resistance leads to right heart failure, and, without treatment, death occurs within 3 years of diagnosis. The etiology of PAH is multifactorial. In some patients, there is a major genetic predisposition in the form of heterozygous germline mutations in a transforming growth factor-β superfamily receptor, the bone morphogenetic type II receptor (BMPR-II). In addition, it is likely that additional factors, such as inflammation, are important to manifest disease. The currently available treatments for PAH were developed mainly as vasodilators, and although they improve symptoms they have limited impact on survival. This review examines the role of the BMPR-II signaling pathway in the process of pulmonary vascular remodeling. We discuss the ways in which manipulation of BMPR-II signaling might be targeted with the aim of preventing or reversing vascular remodeling and improving survival in patients with PAH.
Cellular pathophysiology and therapy of pulmonary hypertension
2001, Journal of Laboratory and Clinical Medicine
Citation Excerpt :
The familial form, an autosomal dominant disease with incomplete penetration, is associated with chromosome 2 q31-33, and this association is also found in asymptomatic relatives with an abnormal pulmonary artery pressure response to exercise.2 Recently, mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene were identified in the majority of families with PPH.3,4 In patients with sporadic PPH, a considerable percentage (about 26%) were also found to exhibit such a defect,5 suggesting that this gene might play an important role in the pathophysiology of PPH and possibly also in some of the associated conditions like appetite-suppressant use.
The identification of several mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor β receptor family, gives hope for new insights into the pathophysiology of pulmonary hypertension. Genetic predisposition might dictate the responses of pulmonary artery fibroblasts, smooth muscle cells, and endothelial cells, as well as platelets and leukocytes, or their specific interactions with different extrinsic factors. These cells possess distinct subtypes and interact with each other. Pulmonary hypertension is associated with vasoconstriction, remodeling, and in situ thrombosis of the pulmonary arteries, but the initial events and their relationship to the genetic background are presently unknown. Current therapeutic approaches are based on our knowledge of the physiologic regulation of pulmonary artery tone, pathophysiologic changes, and our clinical experience with different treatment strategies. Beyond diuretics and anticoagulants, prostaglandins are generally accepted therapeutic agents for primary pulmonary hypertension and related diseases, whereas high-dose calcium-channel blockers are reserved for a small subset of patients, those who respond favorably to vasodilators in an acute test. Long-term intravenous prostacyclin infusion has become the most important specific therapy for primary pulmonary hypertension and associated diseases. However, this therapy is hampered by catheter complications and systemic side effects. Alternative application routes of prostacyclin or its stable analogs may avoid these problems. Inhaled application of the prostacyclin analog iloprost results in predominant pulmonary vasodilation with few systemic side effects and may possess clinical efficacy similar to that of intravenous prostacyclin. Inhaled nitric oxide is widely accepted as a screening agent for active responders to vasodilators and has a similar hemodynamic profile as inhaled iloprost, although the percentage of responders is considerably lower. However, there are unsolved toxicologic questions and practical difficulties concerning the safe long-term application of nitric oxide. Combining inhaled vasodilators with phosphodiesterase inhibitors may prolong the duration of the effects and improve the convenience of inhaled therapy for pulmonary hypertension. Therapeutic approaches in the future may aim at the transforming growth factor β pathway and at the identification of early stages of the disease to prevent further disease progression. (J Lab Clin Med 2001;138:367-77)
BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension
2001, American Journal of Human Genetics
Citation Excerpt :
However, until recently the etiology of PPH has been poorly understood. Linkage analysis in affected families mapped the familial PPH locus to chromosome 2q33, with no evidence for locus heterogeneity (Morse et al. 1997; Nichols et al. 1997; Deng et al. 2000a; Machado et al. 2000). Using a positional candidate-gene strategy, we and others recently have demonstrated that mutations in the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2) cause familial PPH (Deng et al. 2000b; The International PPH Consortium et al. 2000).
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.
Genetics of primary pulmonary hypertension
2001, Clinics in Chest Medicine
Citation Excerpt :
With the putative locus narrowed to the 5.8-Mb PPH1 regions on 2q33, research focused on candidate genes in this area. Eighty-one potential transcriptional units were identified within the critical interval, including BMPR2. 20,27 Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily of signaling molecules.
PATHOPHYSIOLOGY AND PATHOGENIC MECHANISMS OF PULMONARY HYPERTENSION: ROLE OF MEMBRANE RECEPTORS, ION CHANNELS, AND CA<sup>2+</sup> SIGNALING
2023, Physiological Reviews
BZW1 promotes cell proliferation in prostate cancer by regulating TGF-β1/Smad pathway
2021, Cell Cycle

View all citing articles on Scopus

¹: These authors contributed equally to this paper.

²: Other members of the International PPH Consortium and their institutional affiliations are found in the Acknowledgments.

³: To whom correspondence should be addressed. Telephone: (513) 636-2438. Fax: (513) 636-4373. E-mail: [email protected].

View full text

Regular ArticleA Physical and Transcript Map Based upon Refinement of the Critical Interval for PPH1, a Gene for Familial Primary Pulmonary Hypertension

Abstract

J. Biol. Chem.

Genomics

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Chest

Genomics

Genomics

Biochim. Biophys. Acta

Cell

Analysis of aldehyde oxidase and xanthine dehydrogenase/oxidase as possible candidate genes for autosomal recessive familial amyotrophic lateral sclerosis

Somat. Cell Motil. Gene

Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta

Am. J. Pathol.

Analysis of yeast artificial chromosome clones

Faster sequential genetic linkage computations

Am. Hum. Genet.

Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4

Nat. Genet.

Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity

Genes Dev.

Survival in patients with primary pulmonary hypertension. Results from a national prospective registry

Ann. Intern. Med.

Human Ig superfamily CTLA-4 gene: Chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains

Eur. J. Immunol.

A physical map of 30,000 human genes

Science

Regular Article
A Physical and Transcript Map Based upon Refinement of the Critical Interval for PPH1, a Gene for Familial Primary Pulmonary Hypertension