Skip to main content

Advertisement

SpringerLink
Log in

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections.

Methods

Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis.

Results

WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient’s cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient’s innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients.

Conclusions

Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147:990–1007.

    Article  PubMed  Google Scholar 

  2. Kammermeier J, Dziubak R, Pescarin M, Drury S, Godwin H, Reeve K, et al. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of two years. J Crohn's Colitis. 2017;11:60–9.

    Article  Google Scholar 

  3. Uhlig HH, Schwerd T. From genes to mechanisms: the expanding spectrum of monogenic disorders associated with inflammatory bowel disease. Inflamm Bowel Dis. 2016;22:202–12.

    Article  PubMed  Google Scholar 

  4. Schober T, Magg T, Laschinger M, Rohlfs M, Linhares ND, Puchalka J, et al. A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat Commun. 2017;8:14209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sorte HS, Osnes LT, Fevang B, Aukrust P, Erichsen HC, Backe PH, et al. A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T-cell dysfunction. Mol Genet genomic Med. 2016;4:604–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang Y, Ma CS, Ling Y, Bousfiha A, Camcioglu Y, Jacquot S, et al. Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations. J Exp Med. 2016;213:2413–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alazami AM, Al-Helale M, Alhissi S, Al-Saud B, Alajlan H, Monies D, et al. Novel CARMIL2 mutations in patients with variable clinical dermatitis, infections, and combined immunodeficiency. Front Immunol. 2018;9:203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roncagalli R, Cucchetti M, Jarmuzynski N, Grégoire C, Bergot E, Audebert S, et al. The scaffolding function of the RLTPR protein explains its essential role for CD28 co-stimulation in mouse and human T cells. J Exp Med. 2016;213:2437–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, et al. The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res. 2017;45:D840–5.

    Article  CAS  PubMed  Google Scholar 

  10. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. The 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.

    Article  CAS  PubMed Central  Google Scholar 

  12. Scott EM, Halees A, Itan Y, Spencer EG, He Y, Abdellateef Azab M, et al. Characterization of greater middle eastern genetic variation for enhanced disease gene discovery. Nat Genet. 2016;48:1071–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–82.

    Article  CAS  PubMed  Google Scholar 

  14. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.

    Article  CAS  PubMed  Google Scholar 

  15. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T, et al. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016;44:W344–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42:1–7.

    Article  CAS  Google Scholar 

  18. Zezos P, Patsiaoura K, Nakos A, Mpoumponaris A, Vassiliadis T, Giouleme O, et al. Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy. Color Dis. 2014;16:O420–30.

    Article  CAS  Google Scholar 

  19. Morgenstern S, Brook E, Rinawi F, Shamir R, Assa A. Tissue and peripheral eosinophilia as predictors for disease outcome in children with ulcerative colitis. Dig Liver Dis. 2017;49:170–4.

    Article  PubMed  Google Scholar 

  20. Bin Dhuban K, Piccirillo CA. The immunological and genetic basis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Curr Opin Allergy Clin Immunol. 2015;15:525–32.

    Article  CAS  PubMed  Google Scholar 

  21. Posovszky C. Congenital intestinal diarrheal diseases: a diagnostic and therapeutic challenge. Best Pract Res Clin Gastroenterol. 2016;30:187–211.

    Article  CAS  PubMed  Google Scholar 

  22. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J Allergy Clin Immunol. 2007;119:482–7.

    Article  CAS  PubMed  Google Scholar 

  23. Charbit-Henrion F, Jeverica AK, Bègue B, Markelj G, Parlato M, Avcin SL, et al. Deficiency in mucosa-associated lymphoid tissue lymphoma translocation 1: a novel cause of IPEX-like syndrome. J Pediatr Gastroenterol Nutr. 2017;64:378–84.

    Article  CAS  PubMed  Google Scholar 

  24. Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131:1611–1623.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2013;4:6–11.

    Google Scholar 

  26. Alroqi FJ, Charbonnier LM, Keles S, Ghandour F, Mouawad P, Sabouneh R, et al. DOCK8 deficiency presenting as an IPEX-like disorder. J Clin Immunol. 2017;37:811–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015;135:217–27.

    Article  CAS  PubMed  Google Scholar 

  28. Liang Y, Cucchetti M, Roncagalli R, Yokosuka T, Malzac A, Bertosio E, et al. The lymphoid lineage–specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells. Nat Immunol. 2013;14:858–66.

    Article  CAS  PubMed  Google Scholar 

  29. Matsushima N, Tachi N, Kuroki Y, Enkhbayar P, Osaki M, Kamiya M, et al. Structural analysis of leucine-rich-repeat variants in proteins associated with human diseases. Cell Mol Life Sci. 2005;62:2771–91.

    Article  CAS  PubMed  Google Scholar 

  30. Peters-Golden M, Henderson WR. Leukotrienes. N Engl J Med. 2007;357:1841–54.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patient and his family for participating in this study.

Funding

D.S.S. is supported by the Israel Science Foundation and Jeffrey Modell Foundation grants. S.B.S. is supported by NIH grants HL59561, DK034854, and AI50950; the Helmsley Charitable Trust; and the Wolpow Family Chair in IBD Treatment and Research.

Author information

Author notes

  1. Alina Kurolap and Orly Eshach Adiv contributed equally to this work.

    Dror S. Shouval and Hagit Baris Feldman contributed equally to this work.

Authors and Affiliations

  1. The Genetics Institute, Rambam Health Care Campus, Haifa, Israel

    Alina Kurolap, Maya Steinberg, Adi Mory, Tamar Paperna & Hagit Baris Feldman

  2. The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

    Alina Kurolap, Orly Eshach Adiv, Ron Shaoul, Yaniv Zohar & Hagit Baris Feldman

  3. Pediatric Gastroenterology, Rambam Health Care Campus, Haifa, Israel

    Orly Eshach Adiv & Ron Shaoul

  4. Devision of Newborn Medicine, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    Liza Konnikova

  5. Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA, USA

    Liza Konnikova, Vanessa Mitsialis, Sarah Wall & Scott B. Snapper

  6. Harvard Medical School, Boston, MA, USA

    Liza Konnikova, Vanessa Mitsialis & Scott B. Snapper

  7. Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel

    Lael Werner, Moran Y. Nunberg & Dror S. Shouval

  8. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Lael Werner, Moran Y. Nunberg & Dror S. Shouval

  9. Regeneron Genetics Center, Tarrytown, NY, USA

    Claudia Gonzaga-Jauregui, John D. Overton & Alan R. Shuldiner

  10. Institute of Pathology, Rambam Health Care Campus, Haifa, Israel

    Yaniv Zohar

  11. Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, MA, USA

    Scott B. Snapper

Authors
  1. Alina Kurolap
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Orly Eshach Adiv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liza Konnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lael Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Gonzaga-Jauregui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maya Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vanessa Mitsialis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adi Mory
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Moran Y. Nunberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sarah Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ron Shaoul
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John D. Overton
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alan R. Shuldiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yaniv Zohar
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tamar Paperna
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Scott B. Snapper
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Dror S. Shouval
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hagit Baris Feldman
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Regeneron Genetics Center

Corresponding author

Correspondence to Hagit Baris Feldman.

Ethics declarations

The study was approved by the institutional Helsinki committee, and written informed consent was obtained as customary.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 772 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kurolap, A., Eshach Adiv, O., Konnikova, L. et al. A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant. J Clin Immunol 39, 430–439 (2019). https://doi.org/10.1007/s10875-019-00631-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-019-00631-6

Keywords

Search

Navigation