An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency

Ziv, Alma; Werner, Lael; Konnikova, Liza; Awad, Aya; Jeske, Tim; Hastreiter, Maximilian; Mitsialis, Vanessa; Stauber, Tali; Wall, Sarah; Kotlarz, Daniel; Klein, Christoph; Snapper, Scott B.; Tzfati, Yehuda; Weiss, Batia; Somech, Raz; Shouval, Dror S.

doi:10.1007/s10875-020-00829-z

Cited by 11 publications

(11 citation statements)

References 41 publications

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“…RTEL1 mutations have been associated with dyskeratosis congenita and Hoyeraal–Hreidarsson syndrome ( 31 , 32 ). Ziv et al ( 33 ) found that C.3791G > A in RTEL1 was linked to infantile-onset ulcerative colitis and severe immunodeficiency, which is likely the result of aberrant telomere function in both immune and epithelial cells. Patient 2 harbored the novel c.296C > T in RTEL1 , resulting in the change of proline to leucine at the amino acid position 99 (p.Pro99Leu) in the domain of helicase ATP-binding.…”

Section: Discussionmentioning

confidence: 99%

A Case Series of Pediatric Intestinal Ganglioneuromatosis With Novel Phenotypic and Genotypic Profile

et al. 2022

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IntroductionIntestinal ganglioneuromatosis (IGN) is a rare condition with enteric involvement. Herein, we report a case series of pediatric IGN with a novel phenotypic and genotypic profile.MethodsThe clinical presentation, histopathology, immunochemistry, molecular features, treatment, and prognosis of 3 cases of IGN were assessed.ResultsThe cases involved 3 boys with an age range of 1 year and 4 months to 8 years, mimicking juvenile polyps or pseudomembranous enteritis. One patient carried a novel germline mutation in RTEL1 (c.296C > T/p.Pro99Leu) along with variants in F11 (c.1489C > T/p.Arg497Xaa), NBAS (c.1514delC/p.Pro505Hisfs*15), and FECH (c.315-48T > C/splicing), who died due to intractable inflammation. The other two patients underwent recurrence without significant signs of systemic syndrome or malignant progression.ConclusionThis case series added to the phenotypic and genotypic spectrum of pediatric IGN, which requires the accumulation of more cases and research for in-depth understanding.

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Section: Discussionmentioning

confidence: 99%

A Case Series of Pediatric Intestinal Ganglioneuromatosis With Novel Phenotypic and Genotypic Profile

et al. 2022

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“…Other features include pulmonary fibrosis, liver disease, and cancer predisposition ( 74 , 77 , 78 ). Hoyeraal-Hreidarsson syndrome is a severe form of DC with intrauterine growth retardation, microcephaly, cerebellar hypoplasia and often VEOIBD ( 78 – 81 ), in addition to esophageal and rectal strictures ( 79 – 81 ). Patients with DC have progressive T, B and NK cell lymphopenia ( 77 – 81 ).…”

Section: Defects In T and B Cellsmentioning

confidence: 99%

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

Ouahed

2022

Front. Immunol.

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Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease-undefined (IBD-U). IBD are understood to be multifactorial, involving genetic, immune, microbial and environmental factors. Advances in next generation sequencing facilitated the growing identification of over 80 monogenic causes of IBD, many of which overlap with Inborn errors of immunity (IEI); Approximately a third of currently identified IEI result in gastrointestinal manifestations, many of which are inflammatory in nature, such as IBD. Indeed, the gastrointestinal tract represents an opportune system to study IEI as it consists of the largest mass of lymphoid tissue in the body and employs a thin layer of intestinal epithelial cells as the critical barrier between the intestinal lumen and the host. In this mini-review, a selection of pertinent IEI resulting in monogenic IBD is described involving disorders in the intestinal epithelial barrier, phagocytosis, T and B cell defects, as well as those impairing central and peripheral tolerance. The contribution of disrupted gut-microbiota-host interactions in disturbing intestinal homeostasis among patients with intestinal disease is also discussed. The molecular mechanisms driving pathogenesis are reviewed along with the personalized therapeutic interventions and investigational avenues this growing knowledge has enabled.

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“…49 RTEL1 mutation‐induced natural killer (NK)‐cell deficiency has been identified in several patients with a broad spectrum of clinical manifestations. 4 , 5 , 8 , 9 , 61 RTEL1 ‐deficient bone marrow cells exhibit the impaired proliferative potential of the entire bone marrow and cluster‐of‐differentiation 34 (CD34) positive cells in vitro, with the near total disappearance of these cells after prolonged culture. In vivo, differentiation arrest of B‐cells observed during viral infections resulted in a severe reduction of peripheral B‐cell counts, which in turn resulted in hypogammaglobinemia with an impaired antibody response to specific antigens.…”

Section: Rtel1 Deficiency Promotes Tumorigenesismentioning

confidence: 99%

“… 2 Human cells with RTEL1 mutations exhibit rapid telomere shortening, proliferative exhaustion, increased senescence, and spontaneous apoptosis. Phenotypically, RTEL1 mutations are known to be associated with a host of genetic diseases and disorders, including dyskeratosis congenita (DC) and its severe variant, Hoyeraal–Hreidarsson syndrome (HHs), 3 , 4 , 5 bone marrow failure (BMF), 3 , 4 , 5 , 6 , 7 very early‐onset monogenic inflammatory bowel disease (IBD) and IBD‐like colitis, 5 , 8 , 9 pulmonary fibrosis, 3 , 4 , 10 , 11 , 12 , 13 liver disease 4 , 14 and myeloid neoplasms. 7 , 14 , 15 , 16 Several RTEL1 mutants are also associated with an increased risk of glioma.…”

Section: Introductionmentioning

confidence: 99%

Regulator of telomere elongation helicase 1 gene and its association with malignancy

2022

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Background With the progression of next‐generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression. Recent findings A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine‐rich quadruplex DNA (G4‐DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome‐wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune‐deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1 , thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over‐expression was directed toward G4‐unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre‐malignant cellular compartments. Conclusions Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

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An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency

Cited by 11 publications

References 41 publications

A Case Series of Pediatric Intestinal Ganglioneuromatosis With Novel Phenotypic and Genotypic Profile

A Case Series of Pediatric Intestinal Ganglioneuromatosis With Novel Phenotypic and Genotypic Profile

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

Regulator of telomere elongation helicase 1 gene and its association with malignancy

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