Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32


Primary pulmonary hypertension (PPH)f an often fatal disease, is characterized by elevated pulmonary artery pressures in the absence of a secondary cause1. Endovascular occlusion in the smallest pulmonary arteries occurs by proliferation of cells and matrix, with thrombus and vasospasm2. Diagnosis is often delayed because the initial symptoms of fatigue and dyspnea on exertion are nonspecific and definitive diagnosis requires invasive procedures. The average life expectancy after diagnosis is two to three years with death usually due to progressive right heart failure3. The aetiology of the disease is unknown. Although most cases appear to be sporadic, 6% of cases recorded in the NIH Primary Pulmonary Hypertension Registry are inherited in an autosomal dominant manner with reduced penetrance4–6. Following a genome-wide search using a set of highly polymorphic short tandem repeat (STR) markers and 19 affected individuals from six families, initial evidence for linkage was obtained with two chromosome 2q markers. We subsequently genotyped patients and all available family members for 19 additional markers spanning 40 centiMorgans (cM) on the long arm of chromosome 2. We obtained a maximum two-point lod score of 6.97 at θ=0 with the marker D2S389; multipoint linkage analysis yielded a maximum lod score of 7.86 with the marker D2S311. Haplotype analysis established a minimum candidate interval of 25 cM.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Rubin, L.J. Primary pulmonary hypertension. Chest 104, 236–250 (1993).

    CAS  Article  Google Scholar 

  2. 2

    Loyd, J.E. Atkinson, J.B. Pietra, G.G. Virmani, R. & Newman, J.H. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am. Rev. Respir. Dis. 138, 952–957 (1988).

    CAS  Article  Google Scholar 

  3. 3

    D'Alonzo, G.E. et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med. 115, 343–349 (1991).

    CAS  Article  Google Scholar 

  4. 4

    Rich, S. et al. Primary pulmonary hypertension. A national prospective study. Ann. Intern. Med. 107, 216–223 (1987).

    CAS  Article  Google Scholar 

  5. 5

    Loyd, J.E. et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 152, 93–97 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Loyd, J.E. Primm, R.K. & Newman, J.H. Familial primary pulmonary hypertension: clinical patterns. Am. Rev. Respir. Dis. 129, 194–197 (1984).

    CAS  PubMed  Google Scholar 

  7. 7

    O'Connell, J.R. & Weeks, D.E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nature Genet. 11, 402–408 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Matise, T.C. Perlin, M. & Chakravarti, A. Automated construction of genetic linkage maps using an expert system (Multimap): a human genome linkage map. Nature Genet. 6, 384–390 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Terwilliger, J.D. & Ott, J. Handbook of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1994).

  10. 10

    Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1991).

  11. 11

    Dresdale, D.T. Schultz, M. & Michtom, R.J. Primary pulmonary hypertension: 1 Clinical and hemodynamic study. Am. J. Med. 11, 686–701 (1951).

    CAS  Article  Google Scholar 

  12. 12

    Dresdale, D.T. Michtom, R.J. & Schultz, M. Recent studies in primary pulmonary hypertension including pharmacodynamic observartions on pulmonary vascular resistance. Bull. N.Y. Acad. Med. 30, 195–207 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Morse, J.H. Barst, R.J. & Fotino, M. Familial pulmonary hypertension: immunogenetic findings in four Caucasian kindreds. Am. Rev. Respir. Dis. 145, 787–792 (1992).

    CAS  Article  Google Scholar 

  14. 14

    Girard, T.J. et al. Structure of the human lipoprotein-associated coagulation inhibitor gene. Intron/exon gene organization and localization of the gene to chromosome 2. J. Biol. Chem. 266, 5036–5041 (1991).

    CAS  PubMed  Google Scholar 

  15. 15

    Fernandez-Ruiz, E. Pardo-Manuel de Villena, R. Rodriguez de Cordoba, S. & Sanchez-Madrid, F. Regional localization of the human vitronectin receptor alpha subunit gene(VNRA) to chromosome 2q31–q32. Cytogenet. Cell Genet. 62, 26–28 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Solomon, E. et al. Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family. Proc. Natl. Acad. Sci. USA 82, 3330–3334 (1985).

    CAS  Article  Google Scholar 

  17. 17

    Emanuel, B.S. Cannizzaro, L.A. Seyer, J.M. & Myers, J.C. Human alpha 1(111) and alpha 2(V) procollagen genes are located on the long arm of chromosome 2. Proc. Natl. Acad. Sci. USA 82, 3385–3389 (1985).

    CAS  Article  Google Scholar 

  18. 18

    Acampora, D. et al. The human HOX gene family. Nucl. Acids Res. 17, 10385–10402 (1989).

    CAS  Article  Google Scholar 

  19. 19

    Willems, P.J. Dynamic mutations hit double figures. Nature Genet. 8, 213–215 (1994).

    CAS  Article  Google Scholar 

  20. 20

    Morahan, G. Huang, D. Tait, B.D. Colman, P.G. & Harrison, L.C. Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus. Science 272, 1811–1813 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Schuler, G.D. et al. A gene map of the human genome. Science 274, 540–546 (1996).

    CAS  Article  Google Scholar 

  22. 22

    Abenhaim, L. et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N. Engl. J. Med. 335, 609–616 (1996).

    CAS  Article  Google Scholar 

  23. 23

    Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    CAS  Article  Google Scholar 

  24. 24

    Sheffield, V.C. et al. A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps. Hum. Mol. Genet. 4, 1837–1844 (1995).

    CAS  Article  Google Scholar 

  25. 25

    Murray, J.C. et al. A comprehensive human linkage map with centimorgan density. Science 265, 2049–2054 (1994).

    CAS  Article  Google Scholar 

  26. 26

    Hudson, T.J. et al. An STS-based map of the human genome. Science 270, 1945–1954 (1995).

    CAS  Article  Google Scholar 

  27. 27

    Schaffer, A.A. Gupta, S.K. Shriram, K. & Cottingham, R.W. Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).

    CAS  Article  Google Scholar 

  28. 28

    Cottingham, R.W. Jr. Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Lathrop, G.M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Boehnke, M. Allele frequency estimation from data on relatives. Am. J. Hum. Genet. 48, 22–25 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to David Ginsburg.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nichols, W., Koller, D., Slovis, B. et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet 15, 277–280 (1997).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing