Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum of<i>TTC37</i>and<i>SKIV2L</i>, clinical analysis and future prospects

Bourgeois, P.; Estève, Clothilde; Chaix, C; Béroud, Christophe; Lévy, Nicolas; Fabre, Alexandre; Badens, Catherine

doi:10.1002/humu.23418

Cited by 45 publications

(66 citation statements)

References 42 publications

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“…In this study, we performed WES on a selected subgroup of CVID patients with a classical infectious phenotype combined with autoimmunity, inflammation, and/or malignancy and identified probable and possible disease-causing candidate gene variants through a targeted bioinformatics analysis, focusing on 564 primary immunodeficiency-related genes. This approach resulted in the identification of two previously described gene variants in NFKB1 (21,32), nine novel variants, including variants in STAT3, TNFAIP3, IL-17F, IRAK4, TTC37, DDX41, NLRC3, TNFRSF1A, and PLCG2 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(34)(35)(36) associated with different states of immune dysregulation but not previously associated with CVID, and with possible probable diseasecausing impact according to bioinformatics. Altogether, we identified probable/possible disease-causing variants in nine of 20 patients in this CVID subpopulation.…”

Section: Discussionmentioning

confidence: 99%

“…A novel likely deleterious frameshift S1330fs * 14 variant in tetratricopeptide repeat domain (TTC)37 was found in P15 (Tables 2, 3). Her symptoms were only slightly overlapping with autosomal recessive Tricho-Hepato-Enteric Syndrome (OMIM #222470), which is characterized by intrauterine growth retardation, wooly hair, facial dysmorphism, intractable diarrhea in infancy, and immunodepression, previously associated with mutations in this gene (27). However, some patients have been described with only one mutation, and therefore a weak phenotype might be caused by a heterozygous variant.…”

Section: Identified Variantsmentioning

confidence: 97%

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Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

et al. 2020

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Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Identified Variantsmentioning

confidence: 97%

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

et al. 2020

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“…Then, they examined the lab diagnostic cohort in detail for clinical manifestations. They stated that “for the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment.” 16 …”

Section: Discussionmentioning

confidence: 99%

Trichohepatoenteric syndrome: A rare mutation in SKIV2L gene in the first Balkan reported case

Xinias

Mavroudi

Mouselimis

et al. 2018

SAGE Open Medical Case Reports

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Trichohepatoenteric syndrome or syndromic diarrhea is a rare and severe Mendelian autosomal recessive syndrome characterized by intractable diarrhea, facial and hair abnormalities, liver dysfunction, immunodeficiency and failure to thrive. It has been associated with mutations in TTC37 and SKIV2L genes, which encode proteins of the SKI complex that contributes to the cytosolic degradation of the messenger RNA by the cell’s exosome. We report a case of a male infant who suffered from typical symptoms and signs of trichohepatoenteric syndrome without immunodeficiency. The patient’s genetic testing showed a very rare mutation in SKIV2L gene’s 25 exons (p.Glu1038 fs*7 (c.3112_3140del)). Even though our patient was provided with total parenteral nutrition from birth, the child’s death in the third year of age highlights the severity of the disease and the poor prognosis of this particular type of genetic predisposition.

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“…Further analyses revealed that most THES patients had defects in the immune system with low levels of switched immunoglobulins, highly variable responses to vaccination including unresponsiveness of specific antigens, impaired T cell and NK cell functions such as low production of γ-interferon and abnormal T cell proliferation, and severe Epstein Barr Virus (EBV) infection [77]. It appears that 60% of the THES patients had a genetic deficiency of TTC37 [59] and 40% had a deficiency of SKIV2L [78], and many of those homozygous deficiencies were the results of consanguineous marriage. Since the discovery of THES, a spectrum of disease phenotypes and severity has emerged, and the disease has been reported in multiple racial groups [74,75,79,80,81].…”

Section: Skiv2l or Ski2wmentioning

confidence: 99%

“…Since the discovery of THES, a spectrum of disease phenotypes and severity has emerged, and the disease has been reported in multiple racial groups [74,75,79,80,81]. It has been noticed that THES patients with deficiencies of SKIV2L experienced more severe disease in terms of liver damage and impairment of prenatal growth than those with deficiencies of TTC37 [78]. THES patients with deficiency of Skiv2l but not deficiency of TTC37 exhibited a remarkable type I interferon stimulated gene expression profile [56].…”

Section: Skiv2l or Ski2wmentioning

confidence: 99%

An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex

Zhou

Lai

Luo

et al. 2019

Cells

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At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5 triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3 →5 through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5 caps and destruction of faulty adducts in 5 →3 fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.

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Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum ofTTC37andSKIV2L, clinical analysis and future prospects

Cited by 45 publications

References 42 publications

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

Trichohepatoenteric syndrome: A rare mutation in SKIV2L gene in the first Balkan reported case

An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex

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