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01-06-2016 | Original Paper

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

Authors: La Carpia Francesca, Rendeli Claudia, Clelia Molinario, Milillo Annamaria, Farroni Chiara, Cannelli Natalia, Ausili Emanuele, Paolucci Valentina, Neri Giovanni, Romagnoli Costantino, Sangiorgi Eugenio, Gurrieri Fiorella

Published in: Child's Nervous System | Issue 6/2016

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.

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Kibar Z, Capra V, Gros P (2007) Toward understanding the genetic basis of neural tube defects. Clin. Genet. 71:295–310CrossRefPubMed

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. 32:1–9CrossRefPubMed

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):662–669CrossRefPubMedPubMedCentral

Czeizel AE, Dudás I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 327(26):1832–1835CrossRefPubMed

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. 16:2345–2354CrossRefPubMed

Lynch SA (2005) Non-multifactorial neural tube defects. Am. J. Med. Genet. C: Semin. Med. Genet. 135C:69–76CrossRef

Fleming A, Copp AJ (1998) Embryonic folate metabolism and mouse neural tube defects. Science 280:2107–2109CrossRefPubMed

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 88:653–669CrossRefPubMed

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):1371–1375CrossRefPubMedPubMedCentral

10.

Cai C, Shi O (2014) Genetic evidence in planar cell polarity signaling pathway in human neural tube defects. Front Med 8:68–78CrossRefPubMed

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 94:176–181CrossRefPubMed

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. 33:384–390CrossRefPubMed

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. 356:1432–1437CrossRefPubMed

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. 362:2232–2235CrossRefPubMed

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. 80:76–82CrossRefPubMedPubMedCentral

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. 20:4324–4333CrossRefPubMed

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. 33:1450–1455CrossRefPubMed

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. 21:1496–1503CrossRefPubMedPubMedCentral

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. 239:69–76PubMed

20.

Murdoch JN, Copp AJ (2010) The relationship between sonic hedgehog signaling, cilia, and neural tube defects. Birth Defects Res A Clin Mol Teratol 88:633–652CrossRefPubMedPubMedCentral

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 61:347–354CrossRefPubMed

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. 18:1719–1739CrossRefPubMedPubMedCentral

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. 14:1729–1733PubMedPubMedCentral

24.

Bassuk AG, Kibar Z (2009) Genetic basis of neural tube defects. Semin. Pediatr. Neurol. 16:101–110CrossRefPubMed

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):e54492CrossRefPubMedPubMedCentral

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. 22:1358–1372CrossRefPubMedPubMedCentral

27.

Caspary T, Larkins CE, Anderson KV (2007) The graded response to sonic hedgehog depends on cilia architecture. Dev. Cell 12:767–778CrossRefPubMed

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. 18:4565–4575CrossRefPubMedPubMedCentral

29.

Veltman JA, Brunner HG (2012) De novo mutations in human genetic disease. Nat. Rev. Genet. 13:565–575CrossRefPubMed

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 52:493–497CrossRefPubMed

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 4:186–196CrossRefPubMedPubMedCentral

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) 34:1539–1543CrossRef

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. 38:537–542CrossRefPubMed

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. 516:58–66CrossRefPubMedPubMedCentral

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 457:906–909CrossRefPubMedPubMedCentral

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):5257–5268CrossRefPubMedPubMedCentral

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 104:33–42CrossRefPubMed

Title: Variants in TNIP1, a regulator of the NF-kB pathway, found in two patients with neural tube defects
Authors: La Carpia Francesca
Rendeli Claudia
Clelia Molinario
Milillo Annamaria
Farroni Chiara
Cannelli Natalia
Ausili Emanuele
Paolucci Valentina
Neri Giovanni
Romagnoli Costantino
Sangiorgi Eugenio
Gurrieri Fiorella
Publication date: 01-06-2016
Publisher: Springer Berlin Heidelberg
Published in: Child's Nervous System / Issue 6/2016
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-016-3087-1

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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