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Mutational analysis of NOG in esophageal atresia and tracheoesophageal fistula patients

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The NOG protein is a secretory antagonist of bone morphogenetic proteins (BMPs). Nog−/− mouse embryos demonstrate proximal esophageal atresia (EA) and distal tracheoesophageal fistula (TEF) compatible with the most common configuration of EA/TEF observed in humans. Four microdeletions that span the NOG locus at 17q22 have been described in human patients having EA/TEF. We investigated the incidence of point mutations in the coding region of the NOG gene in human EA/TEF.


DNA was collected from 50 patients previously treated for EA/TEF. PCR was used to amplify the coding region of NOG. To detect single nucleotide polymorphisms (SNPs), amplicons were subjected to temperature gradient capillary electrophoresis (TGCE). Candidate SNPs were directly sequenced.


TGCE analysis revealed a SNP in the coding region of NOG in 1 of 50 patients (2%). DNA sequencing revealed a synonymous SNP at position 468 (C–T) of the NOG coding region.


SNPs in the coding region of the NOG gene are identified infrequently in human cases of EA/TEF. Further investigation of SNPs in the promoter region of NOG is warranted, as is the effect of synonymous SNPs on NOG mRNA stability.

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  1. Shaw-Smith C (2006) Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J Med Genet 43(7):545–554. doi:10.1136/jmg.2005.038158

    Article  PubMed  CAS  Google Scholar 

  2. Holder TM, Ashcraft KW (1966) Esophageal atresia and tracheoesophageal fistula. Curr Probl Surg 3(8):2–68

    Google Scholar 

  3. Berrebi D, Lebras MN, Belarbi N, Couturier J, Fattet S, Faye A, Peuchmaur M, de Lagausie P (2006) Bilateral adrenal neuroblastoma and nephroblastoma occurring synchronously in a child with Fanconi’s anemia and VACTERL syndrome. J Pediatr Surg 41(1):e11–e14. doi:10.1016/j.jpedsurg.2005.10.087

    Article  PubMed  Google Scholar 

  4. van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B, van Beusekom E, Rieu P, Newbury-Ecob RA, Chiang C, Brunner HG (2005) MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat Genet 37(5):465–467. doi:10.1038/ng1546

    Article  PubMed  Google Scholar 

  5. Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z, Keng WT, Sharkey FH, McGill N, Hill CJ, Schneider A, Messina M, Turnpenny PD, Fantes JA, van Heyningen V, FitzPatrick DR (2006) Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 15(9):1413–1422. doi:10.1093/hmg/ddl064

    Article  PubMed  CAS  Google Scholar 

  6. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36(9):955–957. doi:10.1038/ng1407

    Article  PubMed  CAS  Google Scholar 

  7. Ondrey F, Griffith A, Van Waes C, Rudy S, Peters K, McCullagh L, Biesecker LG (2000) Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome. Am J Med Genet 94(1):64–67. doi:10.1002/1096-8628(20000904)94:1<64

    Article  PubMed  CAS  Google Scholar 

  8. De Falco F, Cainarca S, Andolfi G, Ferrentino R, Berti C, Rodriguez Criado G, Rittinger O, Dennis N, Odent S, Rastogi A, Liebelt J, Chitayat D, Winter R, Jawanda H, Ballabio A, Franco B, Meroni G (2003) X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A 120A(2):222–228. doi:10.1002/ajmg.a.10265

    Article  PubMed  Google Scholar 

  9. Chittmittrapap S, Spitz L, Kiely EM, Brereton RJ (1989) Oesophageal atresia and associated anomalies. Arch Dis Child 64(3):364–368

    Article  PubMed  CAS  Google Scholar 

  10. Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK, Bolivar J, Bauer M, Zackai EH, McDonald-McGinn D, Nowaczyk MM, Murray M, Hustead V, Mascotti K, Schultz R, Hallam L, McRae D, Nicholson AG, Newbury R, Durham-O’Donnell J, Knight G, Kini U, Shaikh TH, Martin V, Tyreman M, Simonic I, Willatt L, Paterson J, Mehta S, Rajan D, Fitzgerald T, Gribble S, Prigmore E, Patel A, Shaffer LG, Carter NP, Cheung SW, Langston C, Shaw-Smith C (2009) Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 84(6):780–791. doi:10.1016/j.ajhg.2009.05.005

    Article  PubMed  CAS  Google Scholar 

  11. Li Y, Litingtung Y, Ten Dijke P, Chiang C (2007) Aberrant Bmp signaling and notochord delamination in the pathogenesis of esophageal atresia. Dev Dyn 236(3):746–754. doi:10.1002/dvdy.21075

    Article  PubMed  CAS  Google Scholar 

  12. Smith WC, Harland RM (1992) Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 70(5):829–840. pii: 0092-8674(92)90316-5

    Article  PubMed  CAS  Google Scholar 

  13. Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FP, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M, Francomano CA, Warman ML (1999) Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21(3):302–304. doi:10.1038/6821

    Article  PubMed  CAS  Google Scholar 

  14. Krakow D, Reinker K, Powell B, Cantor R, Priore MA, Garber A, Lachman RS, Rimoin DL, Cohn DH (1998) Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21–22. Am J Hum Genet 63(1):120–124. doi:10.1086/301921

    Article  PubMed  CAS  Google Scholar 

  15. Brunet LJ, McMahon JA, McMahon AP, Harland RM (1998) Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280(5368):1455–1457

    Article  PubMed  CAS  Google Scholar 

  16. Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM (2002) Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet 71(3):618–624. doi:10.1086/342067

    Article  PubMed  CAS  Google Scholar 

  17. Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K, Nishimura G, Saito H, Takada G (2001) Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Genet 60(6):447–451. pii: 600607

    Article  PubMed  CAS  Google Scholar 

  18. Khalifa MM, MacLeod PM, Duncan AM (1993) Additional case of de novo interstitial deletion del(17)(q21.3q23) and expansion of the phenotype. Clin Genet 44(5):258–261

    Article  PubMed  CAS  Google Scholar 

  19. Park JP, Moeschler JB, Berg SZ, Bauer RM, Wurster-Hill DH (1992) A unique de novo interstitial deletion del(17)(q21.3q23) in a phenotypically abnormal infant. Clin Genet 41(1):54–56

    Article  PubMed  CAS  Google Scholar 

  20. Dallapiccola B, Mingarelli R, Digilio C, Obregon MG, Giannotti A (1993) Interstitial deletion del(17) (q21.3q23 or 24.2) syndrome. Clin Genet 43(1):54–55

    PubMed  CAS  Google Scholar 

  21. Marsh AJ, Wellesley D, Burge D, Ashton M, Browne C, Dennis NR, Temple K (2000) Interstitial deletion of chromosome 17 (del(17)(q22q23.3)) confirms a link with oesophageal atresia. J Med Genet 37(9):701–704

    Article  PubMed  CAS  Google Scholar 

  22. Levin ML, Shaffer LG, Lewis R, Gresik MV, Lupski JR (1995) Unique de novo interstitial deletion of chromosome 17, del(17) (q23.2q24.3) in a female newborn with multiple congenital anomalies. Am J Med Genet 55(1):30–32. doi:10.1002/ajmg.1320550110

    Article  PubMed  CAS  Google Scholar 

  23. Mickelson EC, Robinson WP, Hrynchak MA, Lewis ME (1997) Novel case of del(17)(q23.1q23.3) further highlights a recognizable phenotype involving deletions of chromosome (17)(q21q24). Am J Med Genet 71(3):275–279. doi:10.1002/(SICI)1096-8628(19970822)71:3<275

    Google Scholar 

  24. Puusepp H, Zilina O, Teek R, Mannik K, Parkel S, Kruustuk K, Kuuse K, Kurg A, Ounap K (2009) 5.9 Mb microdeletion in chromosome band 17q22–q23.2 associated with tracheo-esophageal fistula and conductive hearing loss. Eur J Med Genet 52(1):71–74. doi:10.1016/j.ejmg.2008.09.006

    Article  PubMed  Google Scholar 

  25. Li Q, Liu Z, Monroe H, Culiat CT (2002) Integrated platform for detection of DNA sequence variants using capillary array electrophoresis. Electrophoresis 23(10):1499–1511. doi:10.1002/1522-2683(200205)23:10<1499

    Article  PubMed  CAS  Google Scholar 

  26. Hunt R, Sauna ZE, Ambudkar SV, Gottesman MM, Kimchi-Sarfaty C (2009) Silent (synonymous) SNPs: should we care about them? Methods Mol Biol 578:23–39. doi:10.1007/978-1-60327-411-1_2

    Article  PubMed  CAS  Google Scholar 

  27. Potti TA, Petty EM, Lesperance MM (2011) A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD). Hum Mutat 32(8):877–886. doi:10.1002/humu.21515

    Article  PubMed  CAS  Google Scholar 

  28. Felix JF, de Jong EM, Torfs CP, de Klein A, Rottier RJ, Tibboel D (2009) Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: an overview of the current concepts. Birth Defects Res A Clin Mol Teratol 85(9):747–754. doi:10.1002/bdra.20592

    Article  PubMed  CAS  Google Scholar 

  29. Borovecki F, Jelic M, Grgurevic L, Sampath KT, Bosukonda D, Vukicevic S (2004) Bone morphogenetic protein-7 from serum of pregnant mice is available to the fetus through placental transfer during early stages of development. Nephron Exp Nephrol 97(1):e26–e32. doi:10.1159/000077595

    Article  PubMed  CAS  Google Scholar 

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This manuscript is dedicated in loving memory of our colleague and co-author, Joshua B. Pietsch (1975–2010), whose tireless efforts, despite a chronic neurodegenerative disease that ultimately claimed his life, made this study possible. The authors would also like to acknowledge Andrew C. Ward for helping with sample preparation and DNA extraction.

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The authors declare that they have no conflicts of interest.

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Correspondence to Andrew J. Murphy.

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Murphy, A.J., Li, Y., Pietsch, J.B. et al. Mutational analysis of NOG in esophageal atresia and tracheoesophageal fistula patients. Pediatr Surg Int 28, 335–340 (2012).

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