Bialellic Mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy

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Fig. 1

References

  1. 1.

    Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, et al. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol. 2013;132(3):656–64.e17.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, et al. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology. 2014;146(4):1028–39.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, et al. Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency. J Allergy Clin Immunol. 2014;134(6):1354–64.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Fischer RT, Friend B, Talmon GA, Grant WJ, Quiros-Tejeira RE, Langnas AN, et al. Intestinal transplantation in children with multiple intestinal atresias and immunodeficiency. Pediatr Transplant. 2014;18(2):190–6.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, et al. Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet. 2013;50(5):324–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Notarangelo LD. Multiple intestinal atresia with combined immune deficiency. Curr Opin Pediatr. 2014;26(6):690–6.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Vaillancourt FH, Brault M, Pilote L, Uyttersprot N, Gaillard ET, Stoltz JH, et al. Evaluation of phosphatidylinositol-4-kinase IIIalpha as a hepatitis C virus drug target. J Virol. 2012;86(21):11595–607.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Yang W, Lee PP, Thong MK, Ramanujam TM, Shanmugam A, Koh MT, et al. Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency. Clin Genet. 2015;88(6):542–9.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, et al. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest. 2014;124(1):328–37.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, Haddad E, et al. Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort. Medicine. 2014;93(29):e327.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Agarwal NS, Northrop L, Anyane-Yeboa K, Aggarwal VS, Nagy PL, Demirdag YY. Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency. J Clin Immunol. 2014;34(6):607–10.

    Article  PubMed  Google Scholar 

  12. 12.

    Ngan B, et al. Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia. LymphoSign J. 2014;01(01):10–26.

    Article  Google Scholar 

  13. 13.

    Leclerc-Mercier S, Lemoine R, Bigorgne AE, Sepulveda F, Leveau C, Fischer A, et al. Ichthyosis as the dermatological phenotype associated with TTC7A mutations. Br J Dermatol. 2016, 2016; doi:10.1111/bjd.14644.

  14. 14.

    Baskin JM, Wu X, Christiano R, Oh MS, Schauder CM, Gazzerro E, et al. The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nat Cell Biol. 2016 01//print;18(1):132–8.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Sinisa Savic.

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The authors declare that they have no conflict of interest.

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Capsule Summary

TTC7A deficiency typically causes severe gastrointestinal manifestations such as multiple intestinal atresia or early-onset inflammatory bowel disease. In some cases, this is associated with severe combined immunodeficiency. Partial loss-of-function mutations appear to be associated with a milder phenotype resulting in common variable immunodeficiency-like condition with enteropathy.

Electronic supplementary material

Fig E1
figure2

Sanger sequence electropherogram of pedigree. Sanger sequence electropherogram of the proband II.ii for exon 16/20 c.1817 aAg/aGg (K606R) and exon 17/20 c.2014 Tct/Cct (S672P). Heterozygosity of A1817G paternally I.i and T2014C maternally I.ii. Healthy siblings II.i, II.iii and II.iv (arranged by age left to right on pedigree) show no presence of affected alleles. (GIF 71 kb)

Fig E2
figure3

Ribbon structure model of TTC7A and tetratricopeptide repeat domains. All known pathogenic variants in apoptotic enterocolitis, multiple intestinal atresias, combined immunodeficiency, and enteropathy-lymphocytopenia-alopecia are mapped. Annotation colors match that of the gene representation of Fig. 1 A. Protein changes, purple; stop codon, red; frame shift, green; exon skipping causing variants, orange; retained intron, blue. Tetratricopeptide repeat domains (TPR) are identified as cartoons also corresponding to horizontal bars shown in Fig. 1 A. Tetratricopeptide repeat domains (1–9) 121–157 and 177–210 Red, 414–447 orange, 497–531 yellow, 533–565 Green, 566–599 Cyan, 745–778 Blue, 780–812 Purple, 813–846 Magenta. (GIF 215 kb)

High resolution image (TIFF 25622 kb)

High resolution image (TIFF 6622 kb)

Fig E3

Modeling report. Detailed template report for data used with Phyre2 software indicating alignment, coverage, confidence and % i.d. Template Information 1–20 used for model construction. (PDF 858 kb)

Fig E4

Sequence structure report. Phyre2 software report of secondary structure and disorder prediction showing disorder confidence and conserved domain information. (PDF 172 kb)

Table E1

(DOCX 41 kb)

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Lawless, D., Mistry, A., Wood, P.M. et al. Bialellic Mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy. J Clin Immunol 37, 617–622 (2017). https://doi.org/10.1007/s10875-017-0427-1

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