Recombination as a mechanism for sporadic mutation in the surfactant protein-C gene† ‡
Amy D. McBee MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorDaniel J. Wegner MS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorChristopher S. Carlson PhD
Division of Public Health Sciences, The Fred Hutchinson Cancer Research Center, Seattle, Washington
Search for more papers by this authorJennifer A. Wambach MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorPing Yang MS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorHillary B. Heins BS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorOla D. Saugstad MD
Department of Pediatric Research, Rikshospitalet Faculty of Medicine, University of Oslo, Oslo, Norway
Search for more papers by this authorMichelle A. Trusgnich MS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorJulie Watkins-Torry BA
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorLawrence M. Nogee MD
Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
Search for more papers by this authorHoward Henderson MD
Department of Chemical Pathology, University of Cape Town and NHLS, Cape Town, South Africa
Search for more papers by this authorF. Sessions Cole MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorCorresponding Author
Aaron Hamvas MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Division of Newborn Medicine, St. Louis Children's Hospital, One Children's Place, St. Louis, MO 63110.Search for more papers by this authorAmy D. McBee MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorDaniel J. Wegner MS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorChristopher S. Carlson PhD
Division of Public Health Sciences, The Fred Hutchinson Cancer Research Center, Seattle, Washington
Search for more papers by this authorJennifer A. Wambach MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorPing Yang MS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorHillary B. Heins BS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorOla D. Saugstad MD
Department of Pediatric Research, Rikshospitalet Faculty of Medicine, University of Oslo, Oslo, Norway
Search for more papers by this authorMichelle A. Trusgnich MS
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorJulie Watkins-Torry BA
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorLawrence M. Nogee MD
Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
Search for more papers by this authorHoward Henderson MD
Department of Chemical Pathology, University of Cape Town and NHLS, Cape Town, South Africa
Search for more papers by this authorF. Sessions Cole MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Search for more papers by this authorCorresponding Author
Aaron Hamvas MD
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
Division of Newborn Medicine, St. Louis Children's Hospital, One Children's Place, St. Louis, MO 63110.Search for more papers by this authorThis work was presented, in part, at the Pediatric Academic Societies' Annual Meeting, Toronto, Canada, May 2007 (E-PAS2007:616292.10).
Conflict of interest statement: Dr. McBee's support from Discovery Labs, Inc. did not introduce any bias into this work. None of the authors has a conflict of interest.
Abstract
Objective
To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC.
Study Design
Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D′), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (±50 kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n = 11) and in individuals with the common SFTPB mutation (121ins2, n = 30).
Results
We detected strong evidence (weak LD and BFs > 1,400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in four of five families; the remaining child had evidence for somatic recombination on the mutated allele.
Conclusions
In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC. Pediatr Pulmonol. 2008; 43:443–450. © 2008 Wiley-Liss, Inc.
Supporting Information
This article contains supplementary material, which may be viewed at the Pediatric Pulmonology website at http://www.interscience.wiley.com/jpages/8755-6863/suppmat/index.html .
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Whitsett J, Weaver TE. Mechanisms of disease: hydrophobic surfactant proteins in lung function and disease. N Engl J Med 2002; 347: 2141–2148.
- 2 Beers M, Lomax CA, Russo SJ. Synthetic processing of Surfactant Protein C by alveolar epithelial cells. J Biol Chem 1998; 273: 15287–15293.
- 3 Nogee L, Garnier G, Dietz HC, Singer L, Murphy AM, deMello DE, Colten HR. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest 1994; 93: 1860–1863.
- 4 Cole F, Hamvas A, Rubinstein P, King E, Trusgnich M, Nogee LM, deMello DE, Colten HR. Population-based estimates of surfactant protein B deficiency. Pediatrics 2000; 105: 538– 541.
- 5 Nogee L, Dunbar AE III, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001; 344: 573–579.
- 6 Thomas A, Lane K, Phillips J, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Resp Crit Care Med 2002; 165: 1322–1328.
- 7 Tredano M, Griese M, Brasch F, Schumacher S, de Blic J, Marque S, Houdayer C, Elion J, Couderc R, Bahuau M. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet 2004; 126A: 18–26.
- 8 Nogee L, de Mello DE, Dehner LP, Colten HR. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med 1993; 328: 406–410.
- 9 Shulenin SNL, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004; 350: 1296–1303.
- 10 Hamvas A, Wegner DJ, Carlson CS, Bergmann KR, Trusgnich MA, Fulton L, Kasai Y, An P, Mardis ER, Wilson RK, Cole FS. Comprehensive genetic variant discovery in the surfactant protein B gene. Pediatr Res 2007; 62: 170–175.
- 11 Tredano M, Cooper DN, Stuhrmann M, Christodoulou J, Chuzhanova NA, Roudot-Thoraval F, Boelle PY, Elion J, Jeanpierre M, Feingold J, couderc R, Bahuau M. Origin of the prevalent SFTPB indel g.1549C > GAA (121ins2) mutation causing surfactant protein B (SP-B) deficiency. Am J Med Genet A 2006; 140: 62–69.
- 12 Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: clinical features and evaluation. Semin Perinatol 2006; 30: 316–326.
- 13 Cameron H, Somaschini M, Carrera P, Hamvas A, Whitsett JA, Wert SE, Deutsch G, Nogee LM. A common mutation in the surfactant protein C gene associated with lung disease. J Pediatr 2005; 146: 370–375.
- 14 Hamvas A, Nogee LM, White FV, Schuler P, Hackett BP, Huddleston CB, Mendeloff EN, Hsu FF, Wert SE, Gonzales LW, Beers MF, Ballard PL. Progressive lung disease and surfactant dysfunction with a deletion of surfactant protein C gene. Am J Resp Cell Mol Biol 2004; 30: 771–776.
- 15 Bullard J, Nogee LM. Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein-C gene (SFTPC) mutation. Pediatr Res 2007; 62: 176–179.
- 16 Hamvas A, Trusgnich M, Brice H, Baumgartner J, Hong Y, Nogee LM, Cole FS. Population-based screening for rare mutations: high throughput DNA extraction and amplification from Guthrie cards. Pediatr Res 2001; 50: 666–668.
- 17 Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.
- 18 Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.
- 19 Crawford D, Bhangale T, Li N, Hellenthal G, Rieder MJ, Nickerson DA, Stephens M. Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet 2004; 36: 700–706.
- 20 Kruglyak L, Nickerson DA. Variation is the spice of life. Nat Genet 2001; 27: 234–236.
- 21 Yusen R, Cohen AH, Hamvas A. Normal lung function in subjects heterozygous for surfactant protein B deficiency. Am J Resp Crit Care Med 1999; 159: 411–414.
- 22 Hess S, Blake JD, Blake RD. Wide variations in neighbor-dependent substitution rates. J Mol Biol 1994; 236: 1022–1033.
- 23 Neale M, Keeney S. Clarifying the mechanics of DNA strand exchange in meiotic recombination. Nature 2006; 442: 153–158.
- 24 Berlin S, Brandstrom M, Backstrom N, Axelsson E, Smith N, Ellegren H. Substitution rate heterogeneity and the male mutation bias. J Mol Evol 2006; 62: 226–233.
- 25 Carlson K, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA, Goodfellow PJ. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 1994; 55: 1076–1082.
- 26 Ardlie K, Liu-Cordero SN, Eberle MA, Daly M, Barrett J, Winchester E, Lander ES, Krugylak L. Lower-than-expected linkage disequilibrium between tightly linked markersin humans suggests a role for gene conversion. Am J Hum Genet 2001; 69: 582–589.
- 27 Helleday T. Pathways for mitotic homologous recombination in mammalian cells. Mut Res 2003; 532: 103–115.
- 28 Erickson R. Somatic gene mutation and human disease other than cancer. Mut Res 2003; 543: 125–136.
- 29 Gollob M, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Eng J Med 2006; 345: 2677–2688.
- 30 Beck J, Poulter M, Campbell TA, Uphill JB, Adamson G, Gedes JF, Revesz T, Davis MB, Wood NW, Collinge J, Tabrizi SJ. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum Mol Genet 2004; 13: 1219–1224.
- 31 Franz D. Diagnosis and management of Tuberous Sclerosis Complex. Semin Pediatr Neurol 1998; 5: 253–268.
- 32 Lee N, Norton JA. Multiple endocrine neoplasia type 2B–genetic basis and clinical expression. Surg Oncol 2000; 9: 111–118.
- 33 Russell K, Ming JE, Patel K, Jukofsky L, Magnusson M, Krantz ID. Dominant paternal transmission of Cornelia de Lange Syndrome: a new case and review of 25 previously reported familial recurrences. Am J Med Genet 2001; 104: 267–276.
- 34 Lacz NL, Schwartz RA, Kihiczak G. Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event. Int J Dermatol 2005; 44: 1–6.
Citing Literature
