Login Register Cart 0
Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Case Report

Novel CARMIL2 (RLTPR) Mutation Presenting with Hyper-IgE and Eosinophilia: A Case Report

Author(s): Raha Zamani*, Samaneh Zoghi*, Sepideh Shahkarami, Simin Seyedpour, Raúl Jimenez Heredia, Kaan Boztug and Nima Rezaei*

Volume 24, Issue 5, 2024

Published on: 04 October, 2023

Page: [596 - 605] Pages: 10

DOI: 10.2174/0118715303263327230922043929

Price: $65

Abstract

Background: Inborn errors of immunity are a growing group of disorders with a wide spectrum of genotypic and phenotypic profiles. CARMIL2 (previously named RLTPR) deficiency is a recently described cause of immune dysregulation, mainly presenting with allergy, mucocutaneous infections, and inflammatory bowel disease. CARMIL2 deficiency is categorized under diseases of immune dysregulation with susceptibility to lymphoproliferative conditions.

Case Presentation: Here we describe a 29-years-old male from a consanguineous family, with food and sting allergy, allergic rhinitis, facial molluscum contagiosum (viral infection of the skin in the form of umbilicated papules), eosinophilia and highly elevated serum IgE level. Whole exome sequencing revealed numerous homozygous variants, including a CARMIL2 nonsense mutation, a gene regulating actin polymerization, and promoting cell protrusion formation.

Conclusion: The selective role of CARMIL2 in T cell activation and maturation through cytoskeletal organization is proposed to be the cause of immune dysregulation in individuals with CARMIL2 deficiency. CARMIL2 has an important role in immune pathways regulation, through cell maturation and differentiation, giving rise to a balance between Th1, Th2, and Th17 immune response. This case can improve the understanding of the different impacts of CARMIL2 mutations on immune pathways and further guide the diagnosis of patients with similar phenotypes.

Keywords: Inborn errors of immunity, CARMIL2-deficiency, molluscum contagiosum, Hyper-IgE syndromes, diseases of immune dysregulation, whole-exome sequencing.

« Previous Next »
Graphical Abstract

[1]
Tangye, S.G.; Al-Herz, W.; Bousfiha, A.; Cunningham-Rundles, C.; Franco, J.L.; Holland, S.M.; Klein, C.; Morio, T.; Oksenhendler, E.; Picard, C.; Puel, A.; Puck, J.; Seppänen, M.R.J.; Somech, R.; Su, H.C.; Sullivan, K.E.; Torgerson, T.R.; Meyts, I. Human inborn errors of immunity: 2022 update on the classification from the international union of immunological societies expert committee. J. Clin. Immunol., 2022, 42(7), 1473-1507.
[http://dx.doi.org/10.1007/s10875-022-01289-3] [PMID: 35748970]
[2]
Liang, Y.; Cucchetti, M.; Roncagalli, R.; Yokosuka, T.; Malzac, A.; Bertosio, E.; Imbert, J.; Nijman, I.J.; Suchanek, M.; Saito, T.; Wülfing, C.; Malissen, B.; Malissen, M. 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(8), 858-866.
[http://dx.doi.org/10.1038/ni.2634] [PMID: 23793062]
[3]
Roncagalli, R.; Cucchetti, M.; Jarmuzynski, N.; Grégoire, C.; Bergot, E.; Audebert, S.; Baudelet, E.; Menoita, M.G.; Joachim, A.; Durand, S.; Suchanek, M.; Fiore, F.; Zhang, L.; Liang, Y.; Camoin, L.; Malissen, M.; Malissen, B. 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(11), 2437-2457.
[http://dx.doi.org/10.1084/jem.20160579] [PMID: 27647348]
[4]
Kurolap, A.; Eshach, A.,O.; Konnikova, L.; Werner, L.; Gonzaga-Jauregui, C.; Steinberg, M.; Mitsialis, V.; Mory, A.; Nunberg, M.Y.; Wall, S.; Shaoul, R.; Overton, J.D.; Shuldiner, A.R.; Zohar, Y.; Paperna, T.; Snapper, S.B.; Shouval, D.S.; Baris F., H. A unique presentation of infantile-onset colitis and eosinophilic disease without recurrent infections resulting from a novel homozygous CARMIL2 variant. J. Clin. Immunol., 2019, 39(4), 430-439.
[http://dx.doi.org/10.1007/s10875-019-00631-6] [PMID: 31079270]
[5]
Maccari, M.E.; Speckmann, C.; Heeg, M.; Reimer, A.; Casetti, F.; Has, C.; Ehl, S.; Castro, C.N. Profound immunodeficiency with severe skin disease explained by concomitant novel CARMIL2 and PLEC1 loss-of-function mutations. Clin. Immunol., 2019, 208, 108228.
[http://dx.doi.org/10.1016/j.clim.2019.06.004] [PMID: 31195081]
[6]
Shayegan, L.H.; Garzon, M.C.; Morel, K.D.; Borlack, R.; Vuguin, P.M.; Margolis, K.G.; Demirdag, Y.Y.; Pereira, E.M.; Lauren, C.T. CARMIL2 ‐related immunodeficiency manifesting with photosensitivity. Pediatr. Dermatol., 2020, 37(4), 695-697.
[http://dx.doi.org/10.1111/pde.14173] [PMID: 32342551]
[7]
Atschekzei, F.; Jacobs, R.; Wetzke, M.; Sogkas, G.; Schröder, C. Ah renstorf, G.; Dhingra, A.; Ott, H.; Baumann, U.; Schmidt, R.E. A novel CARMIL2 mutation resulting in combined immunodeficiency manifesting with dermatitis, fungal, and viral skin infections as well as selective antibody deficiency. J. Clin. Immunol., 2019, 39(3), 274-276.
[http://dx.doi.org/10.1007/s10875-019-00628-1] [PMID: 31001706]
[8]
Sorte, H.S.; Osnes, L.T.; Fevang, B.; Aukrust, P.; Erichsen, H.C.; Backe, P.H.; Abrahamsen, T.G.; Kittang, O.B.; Øverland, T.; Jhangiani, S.N.; Muzny, D.M.; Vigeland, M.D.; Samarakoon, P.; Gambin, T.; Akdemir, Z.H.C.; Gibbs, R.A.; Rødningen, O.K.; Lyle, R.; Lupski, J.R.; Stray-Pedersen, A. 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(6), 604-616.
[http://dx.doi.org/10.1002/mgg3.237] [PMID: 27896283]
[9]
Alazami, A.M.; Al-Helale, M.; Alhissi, S.; Al-Saud, B.; Alajlan, H.; Monies, D.; Shah, Z.; Abouelhoda, M.; Arnaout, R.; Al-Dhekri, H.; Al-Numair, N.S.; Ghebeh, H.; Sheikh, F.; Al-Mousa, H. Novel CARMIL2 mutations in patients with variable clinical dermatitis, infections, and combined immunodeficiency. Front. Immunol., 2018, 9, 203.
[http://dx.doi.org/10.3389/fimmu.2018.00203] [PMID: 29479355]
[10]
Kolukisa, B.; Baser, D.; Akcam, B.; Danielson, J.; Bilgic Eltan, S.; Haliloglu, Y.; Sefer, A.P.; Babayeva, R.; Akgun, G.; Charbonnier, L.M.; Schmitz-Abe, K.; Kendir Demirkol, Y.; Zhang, Y.; Gonzaga-Jauregui, C.; Jimenez Heredia, R.; Kasap, N.; Kiykim, A.; Ozek Yucel, E.; Gok, V.; Unal, E.; Pac Kisaarslan, A.; Nepesov, S.; Baysoy, G.; Onal, Z.; Yesil, G.; Celkan, T.T.; Cokugras, H.; Camcioglu, Y.; Eken, A.; Boztug, K.; Lo, B.; Karakoc-Aydiner, E.; Su, H.C.; Ozen, A.; Chatila, T.A.; Baris, S. Evolution and long‐term outcomes of combined immunodeficiency due to CARMIL2 deficiency. Allergy, 2022, 77(3), 1004-1019.
[http://dx.doi.org/10.1111/all.15010] [PMID: 34287962]
[11]
Magg, T.; Shcherbina, A.; Arslan, D.; Desai, M.M.; Wall, S.; Mitsialis, V.; Conca, R.; Unal, E.; Karacabey, N.; Mukhina, A.; Rodina, Y.; Taur, P.D.; Illig, D.; Marquardt, B.; Hollizeck, S.; Jeske, T.; Gothe, F.; Schober, T.; Rohlfs, M.; Koletzko, S.; Lurz, E.; Muise, A.M.; Snapper, S.B.; Hauck, F.; Klein, C.; Kotlarz, D. CARMIL2 deficiency presenting as very early onset inflammatory bowel disease. Inflamm. Bowel Dis., 2019, 25(11), 1788-1795.
[http://dx.doi.org/10.1093/ibd/izz103] [PMID: 31115454]
[12]
Matsuzaka, Y.; Okamoto, K.; Mabuchi, T.; Iizuka, M.; Ozawa, A.; Oka, A.; Tamiya, G.; Kulski, J.K.; Inoko, H. Identification, expression analysis and polymorphism of a novel RLTPR gene encoding a RGD motif, tropomodulin domain and proline/leucine-rich regions. Gene, 2004, 343(2), 291-304.
[http://dx.doi.org/10.1016/j.gene.2004.09.004] [PMID: 15588584]
[13]
Wang, Y.; Ma, C.S.; Ling, Y.; Bousfiha, A.; Camcioglu, Y.; Jacquot, S.; Payne, K.; Crestani, E.; Roncagalli, R.; Belkadi, A.; Kerner, G.; Lorenzo, L.; Deswarte, C.; Chrabieh, M.; Patin, E.; Vincent, Q.B.; Müller-Fleckenstein, I.; Fleckenstein, B.; Ailal, F.; Quintana-Murci, L.; Fraitag, S.; Alyanakian, M.A.; Leruez-Ville, M.; Picard, C.; Puel, A.; Bustamante, J.; Boisson-Dupuis, S.; Malissen, M.; Malissen, B.; Abel, L.; Hovnanian, A.; Notarangelo, L.D.; Jouanguy, E.; Tangye, S.G.; Béziat, V.; Casanova, J.L. Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations. J. Exp. Med., 2016, 213(11), 2413-2435.
[http://dx.doi.org/10.1084/jem.20160576] [PMID: 27647349]
[14]
Marangi, G.; Garcovich, S.; Sante, G.; Orteschi, D.; Frangella, S.; Scaldaferri, F.; Genuardi, M.; Peris, K.; Gurrieri, F.; Zollino, M. Complex muco-cutaneous manifestations of CARMIL2-associated combined immunodeficiency: A novel presentation of dysfunctional epithelial barriers. Acta Derm. Venereol., 2020, 100(1), 1-2.
[http://dx.doi.org/10.2340/00015555-3370] [PMID: 31709449]
[15]
Kim, D.; Uner, A.; Saglam, A.; Chadburn, A.; Crane, G.M. Peripheral eosinophilia in primary immunodeficiencies of actin dysregulation: A case series of Wiskott-Aldrich syndrome, CARMIL2 and DOCK8 deficiency and review of the literature. Ann. Diagn. Pathol., 2019, 43, 151413.
[http://dx.doi.org/10.1016/j.anndiagpath.2019.151413] [PMID: 31677488]
[16]
Lanier, M.H.; McConnell, P.; Cooper, J.A. Cell migration and invadopodia formation require a membrane-binding domain of CARMIL2. J. Biol. Chem., 2016, 291(3), 1076-1091.
[http://dx.doi.org/10.1074/jbc.M115.676882] [PMID: 26578515]
[17]
Yonkof, J.R.; Gupta, A.; Rueda, C.M.; Mangray, S.; Prince, B.T.; Rangarajan, H.G.; Alshahrani, M.; Varga, E.; Cripe, T.P.; Abraham, R.S. A novel pathogenic variant in CARMIL2 (RLTPR) causing CARMIL2 deficiency and EBV-associated smooth muscle tumors. Front Immunol., 2020, 11, 884.
[18]
Schober, T.; Magg, T.; Laschinger, M.; Rohlfs, M.; Linhares, N.D.; Puchalka, J.; Weisser, T.; Fehlner, K.; Mautner, J.; Walz, C.; Hussein, K. A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat. Commun., 2017, 8, 14209.

Rights & Permissions Print Cite
Article Metrics
21
3
Wayfinder Image
World Diabetes Day
© 2024 Bentham Science Publishers | Privacy Policy