Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome

Vardi, Iddo; Barel, Ortal; Sperber, Michal; Schvimer, Michael; Nunberg, M; Field, Michael; Ouahed, Jodie; Marek‐Yagel, Dina; Werner, Lael; Haberman, Yael; Lahad, Avishay; Anikster, Yair; Rechavi, Gideon; Barshack, Iris; McElwee, Joshua; Maranville, Joseph C.; Somech, Raz; Snapper, Scott B.; Weiss, Batia; Shouval, Dror S.

doi:10.1007/s10620-018-4983-x

Cited by 12 publications

(8 citation statements)

References 27 publications

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“…The patient was diagnosed with Dubowitz syndrome in Dyment et al, 2021 [45]. Monies et al, 2015;Lee et al, 2016;Zheng et al, 2016;Bick et al, 2017;Hiejima et al, 2017;Bourgeois et al, 2018;Vardi et al, 2018;Rudilla et al, 2019;Fung et al, 2020;Taher et al, 2020;Dyment et al, 2021;Klee et al, 2021), the incidence of this disease is not significantly different between genders (M:F 17:20) (Table 1). Patients have their onset mostly in the neonatal period, ranging from birth to 0.8 years of age (mean, 29.5 days; median, 17 days).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2

et al. 2021

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Background: Trichohepatoenteric syndrome (THES) is a rare disease that mainly causes intractable diarrhea. It is classified into THES1 and THES2, which are associated with the tetratricopeptide repeat domain 37 (TTC37) gene and Ski2-like RNA helicase (SKIV2L) gene, respectively. THES is not very prevalent in China or worldwide, but new cases have increasingly been reported.Methods and Results: Here, we report the clinical and genetic information of a 1.5-month-old girl who was admitted to our hospital due to diarrhea and failure to thrive. Whole-exome sequencing (WES) revealed novel compound-heterozygous variants of the SKIV2L gene, c.3602_3609delAGCGCCTG (p.Q1201Rfs*2), and c.1990A > G (p.T664A) as the causative factors, which were confirmed via Sanger sequencing. Upon continuous feeding with an amino-acid formula through a gastric tube and parenteral nutrition, the patient resumed thriving and her stool frequency decreased.Conclusion: We report a girl carrying novel variants of the SKIV2L gene that cause THES2, thereby providing valuable information on the diagnosis of THES2 and expanding the spectrum of disease-causing SKIV2L mutations.

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Section: Discussionmentioning

confidence: 99%

Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2

et al. 2021

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“…Others in 2018 identified an autosomal recessive C.1891G>A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome in a child with failure to thrive and chronic diarrhea but without hair or facial abnormalities. 14 The authors report that protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, through conformational changes, interference with the protein’s packing or changes at the protein’s interface.…”

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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“…Whole Exome Sequencing (WES) was performed in collaboration with Merck Research Labs using an Agilent v5 Sureselect capture kit and Illumina 2500 sequencing technology as previously described 70 . For each sample, paired end reads (2×100 bp) were obtained, processed and mapped to the human reference genome (hg19).…”

Section: Methodsmentioning

confidence: 99%

Variants in Interferon Lambda are Associated with Very Early Onset Inflammatory Bowel Disease

Ouahed

Broggi

Glick

et al. 2022

Preprint

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Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine that affect children and adults. The etiology is multifactorial with the contribution of genetic, immune, microbial, and environmental risk factors with a substantial involvement of host:microbial cross-talk in the lumen. Whether and how antiviral responses contribute to IBD pathogenesis is under intense investigation. Here, we identified two unrelated patients diagnosed with infantile-onset IBD with rare variants in type III Interferons (IFNs), also known as interferon lambdas, a group of IFNs that play key roles in the protection against enteric viruses. The first patient was found to have homozygous variants in both IFNL2 and IFNL3, the genes encoding, IFN lambda-2 and IFN lambda-3, respectively. The second patient was found to have inherited compound heterozygous variants in IFNL3, with one of the two alleles bearing the same variant as the first patient. Functional analyses revealed that the proteins coded for by these variant IFN-lambda genes exhibited defects in the induction of IFN signaling. More detailed assessment of the variants identified in Patient 1 demonstrated defects in their ability to bind to IFN lambda receptor 1 (IFNLR1), as well as their ability to induce heterodimerization of IFNLR1 and IL10RB, which together compromise the functional receptor for IFN lambda (IFNLR). These patient-encoded IFN lambda variants also exhibit defects in the ability to induce robust downstream IFN-stimulated genes (ISGs) in patient-derived intestinal organoids. All in all, we demonstrate that infantile-onset IBD is associated with variants in IFN lambdas and defective induction of downstream IFN signaling.

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Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome

Abstract: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

Cited by 12 publications

References 27 publications

Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2

Case Report: Novel Compound-Heterozygous Variants of SKIV2L Gene that Cause Trichohepatoenteric Syndrome 2

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

Variants in Interferon Lambda are Associated with Very Early Onset Inflammatory Bowel Disease

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