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Child's Nervous System

, Volume 32, Issue 6, pp 1061–1067 | Cite as

Variants in TNIP1, a regulator of the NF-kB pathway, found in two patients with neural tube defects

  • La Carpia Francesca
  • Rendeli Claudia
  • Clelia Molinario
  • Milillo Annamaria
  • Farroni Chiara
  • Cannelli Natalia
  • Ausili Emanuele
  • Paolucci Valentina
  • Neri Giovanni
  • Romagnoli Costantino
  • Sangiorgi Eugenio
  • Gurrieri FiorellaEmail author
Original Paper

Abstract

Purpose

Neural tube defects (NTDs) occur in 1:1000 births. The etiology is complex, with the influence of environmental and genetic factors. Environmental factors, such as folate deficiency, diabetes, or hypoxia strongly contribute to the occurrence of NTD. Also, there is a strong genetic contribution to NTD, as highlighted by the number of genes so far identified in several different developmental pathways usually altered in NTD. Each gene identified so far accounts for a small percentage of all NTD cases, indicating a very high heterogeneity.

Methods

Exome sequencing was performed in seven sporadic patients with severe mielomeningocele. Novel coding variants shared by two or more patients were selected for further analysis.

Results

We identified in two unrelated patients two different variants in TNIP1, a gene not previously involved in NTD whose main role is downregulation of the NF-kB pathway. One variant, c.1089T>G (p.Phe363Leu), is de novo, whereas the c.1781C>T (p.Pro594Leu) is absent in the mother, but could not be tested in the father, as he was unavailable. The latter variant is a very rare variant in the ExAC database.

Conclusions

These findings suggest that TNIP1 is a new potential predisposing gene to spina bifida (SB) and its pathway needs to be investigated in human NTD in order to confirm its role and to plan appropriate counseling to families.

Keywords

Exome sequencing Spina bifida TNIP1 

Notes

Acknowledgments

We thank the families for contributing to our studies and the Association “La Strada per l’Arcobaleno” for funding it.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

381_2016_3087_MOESM1_ESM.pdf (1.1 mb)
ESM 1 (PDF 1094 kb)

References

  1. 1.
    Kibar Z, Capra V, Gros P (2007) Toward understanding the genetic basis of neural tube defects. Clin. Genet. 71:295–310CrossRefPubMedGoogle Scholar
  2. 2.
    Melvin EC, George TM, Worley G, Franklin A, Mackey J, Viles K, Shah N, Drake CR, Enterline DS, McLone D, Nye J, Oakes WJ, McLaughlin C, Walker ML, Peterson P, Brei T, Buran C, Aben J, Ohm B, Bermans I, Qumsiyeh M, Vance J, Pericak-Vance MASM, George TM, Worley G (2000) Genetic studies in neural tube defects. NTD collaborative group. Pediatr. Neurosurg. 32:1–9CrossRefPubMedGoogle Scholar
  3. 3.
    Deak KL, Siegel DG, George TM, Gregory S, Ashley-Koch, Speer MC, NTD collaborative group (2008) Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth Defects Res A Clin Mol Teratol 82(10):662–669CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Czeizel AE, Dudás I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 327(26):1832–1835CrossRefPubMedGoogle Scholar
  5. 5.
    Dheen ST, Tay SS, Boran J, Ting LW, Kumar SD, Fu J, Ling EA (2009) Recent studies on neural tube defects in embryos of diabetic pregnancy: an overview. Curr. Med. Chem. 16:2345–2354CrossRefPubMedGoogle Scholar
  6. 6.
    Lynch SA (2005) Non-multifactorial neural tube defects. Am. J. Med. Genet. C: Semin. Med. Genet. 135C:69–76CrossRefGoogle Scholar
  7. 7.
    Fleming A, Copp AJ (1998) Embryonic folate metabolism and mouse neural tube defects. Science 280:2107–2109CrossRefPubMedGoogle Scholar
  8. 8.
    Harris MJ, Juriloff DM (2010) An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res A Clin Mol Teratol 88:653–669CrossRefPubMedGoogle Scholar
  9. 9.
    Bosoi CM, Capra V, Allache R, Trinh VQ, De Marco P, Merello E, Drapeau P, Bassuk AG, Kibar Z (2011) Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects. Hum. Mutat. 32(12):1371–1375CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cai C, Shi O (2014) Genetic evidence in planar cell polarity signaling pathway in human neural tube defects. Front Med 8:68–78CrossRefPubMedGoogle Scholar
  11. 11.
    Allache R, De Marco P, Merello E, Capra V, Kibar Z (2012) Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis. Birth Defects Res Part A Clin Mol Teratol 94:176–181CrossRefPubMedGoogle Scholar
  12. 12.
    De Marco P, Merello E, Rossi A, Piatelli G, Cama A, Kibar Z, Capra V (2012) FZD6 is a novel gene for human neural tube defects. Hum. Mutat. 33:384–390CrossRefPubMedGoogle Scholar
  13. 13.
    Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, Kirillova I, Merello E, Hayes JM, Wallingford JB, Drapeay P, Capra V, Gros P (2007) Mutations in VANGL1 associated with neural-tube defects. N. Engl. J. Med. 356:1432–1437CrossRefPubMedGoogle Scholar
  14. 14.
    Lei Y-P, Zhang T, Li H, Wu B, Jin L, Wang HY (2010) VANGL2 mutations in human cranial neural-tube defects. N. Engl. J. Med. 362:2232–2235CrossRefPubMedGoogle Scholar
  15. 15.
    Kibar Z, Salem S, Bosoi C, Pauwels E, De Marco P, Merello E, Bassuk AG, Capra V, Gros P (2011) Contribution of VANGL2 mutations to isolated neural tube defects. Clin. Genet. 80:76–82CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Seo JH, Zilber Y, Babayeva S, Liu J, Kyriakopoulos P, De Marco P, Merello E, Capra V, Gros P, Torban E (2011) Mutations in the planar cell polarity gene, fuzzy, are associated with neural tube defects in humans. Hum. Mol. Genet. 20:4324–4333CrossRefPubMedGoogle Scholar
  17. 17.
    Shi Y, Ding Y, Lei YP, Yang XY, Xie GM, Wen J, Cai CQ, Li H, Chen Y, Zhang T, Wu BL, Jin L, Chen YG, Wang HY (2012) Identification of novel rare mutations of DACT1 in human neural tube defects. Hum. Mutat. 33:1450–1455CrossRefPubMedGoogle Scholar
  18. 18.
    Narisawa A, Komatsuzaki S, Kikuchi A, Niihori T, Aoki Y, Fujiwara K, Tanemura M, Hata A, Suzuki Y, Relton CL, Grinham J, Leung KY, Partridge D, Robinson A, Stone V, Gustavsson P, Stanier P, Copp AJ, Greene ND, Tominaga T, Matsubara Y, Kure S (2012) Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. Hum. Mol. Genet. 21:1496–1503CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ulloa F, Martí E (2010) Wnt won the war: antagonistic role of wnt over Shh controls dorso-ventral patterning of the vertebrate neural tube. Dev. Dyn. 239:69–76PubMedGoogle Scholar
  20. 20.
    Murdoch JN, Copp AJ (2010) The relationship between sonic hedgehog signaling, cilia, and neural tube defects. Birth Defects Res A Clin Mol Teratol 88:633–652CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kirillova I, Novikova I, Augé J, Audollent S, Esnault D, Encha-Razavi F, Lazjuk G, Attie-Bitach T, Vekemans M (2000) Expression of the sonic hedgehog gene in human embryos with neural tube defects. Teratology 61:347–354CrossRefPubMedGoogle Scholar
  22. 22.
    Patterson VL, Damrau C, Paudyal A, Reeve B, Grimes DT, Stewart ME, Williams DJ, Siggers P, Greenfield A, Murdoch JN (2009) Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the sonic hedgehog pathway. Hum. Mol. Genet. 18:1719–1739CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Li Q, Estepa G, Memet S, Marnet S, Israel A, Verma M (2000) Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev. 14:1729–1733PubMedPubMedCentralGoogle Scholar
  24. 24.
    Bassuk AG, Kibar Z (2009) Genetic basis of neural tube defects. Semin. Pediatr. Neurol. 16:101–110CrossRefPubMedGoogle Scholar
  25. 25.
    Chen X, Shen Y, Gao Y, Zhao H, Sheng X, Zou J, Lip V, Xie H, Guo J, Shao H, Bao Y, Shen J, Niu B, Gusella JF, Wu BL, Zhang T (2013) Detection of copy number variants reveals Association of Cilia Genes with neural tube defects. PLoS One 8(1):e54492CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Abdelhamed ZA, Wheway G, Szymanska K, Natarajan S, Toomes C, Inglehearn C, Johonson CA (2013) Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and wnt signalling defects. Hum. Mol. Genet. 22:1358–1372CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Caspary T, Larkins CE, Anderson KV (2007) The graded response to sonic hedgehog depends on cilia architecture. Dev. Cell 12:767–778CrossRefPubMedGoogle Scholar
  28. 28.
    Weatherbee SD, Niswander L, Anderson KV (2009) A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and hedgehog signaling. Hum. Mol. Genet. 18:4565–4575CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Veltman JA, Brunner HG (2012) De novo mutations in human genetic disease. Nat. Rev. Genet. 13:565–575CrossRefPubMedGoogle Scholar
  30. 30.
    Lemay P, Guyot M-C, Tremblay E, Dionne-Laport A, Spiegelman D, Henrion E, Diallo O, De Marco P, Merello E, Massicotte C, Desilets V, Michaud JL, Rouleau GA, Capra V, Kibar Z (2015) Loss-of-function de novo mutations play an important role in severe human neural tube defects. J Med Genet 52:493–497CrossRefPubMedGoogle Scholar
  31. 31.
    McGreevy EM, Vijayraghavan D, Davidson L, Hildebrand JD (2015) Shroom3 functions downstream of planar cell polarity to regulate myosin II distribution and cellular organization during neural tube closure. Biol Open 4:186–196CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Eubanks JD, Cheruvu VK (2009) Prevalence of sacral spina bifida occulta and its relationship to age, sex, race, and the sacral table angle: an anatomic, osteologic study of three thousand one hundred specimens. Spine (Phila Pa 1976) 34:1539–1543CrossRefGoogle Scholar
  33. 33.
    Fidas A, MacDonald HL, Elton RA, Wild SR, Chrisholm GD, Scott R (1987) Prevalence and patterns of spina bifida occulta in 2707 normal adults. Clin. Radiol. 38:537–542CrossRefPubMedGoogle Scholar
  34. 34.
    Flores AM, Gurevich I, Zhang C, Ramirez VP, Devens TR, Aneskievich BJ (2011) TNIP1 is a corepressor of agonist-bound PPARs. Arch. Biochem. Biophys. 516:58–66CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, Shifrin N, Lee B, Benedict Yen TS, Woo T, Malynn BA, Ma A (2009) ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature 457:906–909CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Correa RG, Tergaonkar V, Ng JK, Dubova I, Izpisua-Belmonte JC, Verma IM (2004) Characterization of NF- κ B/I κ B proteins in zebra fish and their involvement in notochord development. Mol. Cell. Biol. 24(12):5257–5268CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ruland J, Duncan GS, Elia A, del Barco BI, Nguyen L, Plyte S, Millar DG, Bouchard D, Wakeham A, Ohashi PS, Mak TW (2001) Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Cell 104:33–42CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • La Carpia Francesca
    • 1
  • Rendeli Claudia
    • 2
  • Clelia Molinario
    • 3
  • Milillo Annamaria
    • 3
  • Farroni Chiara
    • 3
  • Cannelli Natalia
    • 3
  • Ausili Emanuele
    • 2
  • Paolucci Valentina
    • 2
  • Neri Giovanni
    • 3
  • Romagnoli Costantino
    • 2
  • Sangiorgi Eugenio
    • 3
  • Gurrieri Fiorella
    • 3
    Email author
  1. 1.Department of Pathology and Cell BiologyColumbia University Medical CenterColumbiaUSA
  2. 2.Istituto di PediatriaUniversità Cattolica del Sacro Cuore “A. Gemelli”RomeItaly
  3. 3.Istituto di Medicina GenomicaUniversità Cattolica del Sacro Cuore “A. Gemelli”RomeItaly

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