Human
            <scp>ALPI</scp>
            deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Parlato, Marianna; Charbit‐Henrion, Fabienne; Pan, Jie; Romano, Claudio; Duclaux-Loras, Rémi; Du, Marie-Hélène Le; Warner, Neil; Francalanci, Paola; Bruneau, Julie; Bras, Marc; Zarhrate, Mohammed; Bègue, Bernadette; Guégan, Nicolas; Rakotobé, Sabine; Kapel, Nathalie; Angelis, Paola De; Griffiths, Anne M.; Fiedler, Karoline; Crowley, Eileen; Ruemmele, Frank M; Muise, Aleixo M.; Cerf‐Bensussan, Nadine

doi:10.15252/emmm.201708483

Cited by 51 publications

(35 citation statements)

References 43 publications

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“…In our cohort, WES allowed us to ascribe VEO-IBD to biallelic mutations in DUOX2 , 41 and more recently to biallelic mutations in intestinal alkaline phosphatase. 42 Furthermore, novel candidate genes are currently under validation in three distinct families.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Charbit‐Henrion

Parlato

Hanein

et al. 2018

Journal of Crohn's and Colitis

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Background and AimsAn expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment.MethodsA total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally.ResultsMolecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES.ConclusionsOur results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

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Section: Discussionmentioning

confidence: 99%

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Charbit‐Henrion

Parlato

Hanein

et al. 2018

Journal of Crohn's and Colitis

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“…Gata 4 is a marker of intestinal epithelial differentiation that is essential to preserve gut barrier function and mucosal integrity ( Lepage et al, 2016 ). Intestinal alkaline phosphatase (Alpi) is a brush border enzyme that considerably diminishes the pro−inflammatory action of LPS ( Parlato et al, 2018 ). Dipeptidyl peptidase ( Dpp4) expression is increased in inflammatory bowel disease, atherosclerosis, obesity, and multiple sclerosis, implying its participation in the pathogenesis of inflammation ( Zhou et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Intestinal Lipid Metabolism Genes Regulated by miRNAs

Ruiz-Roso¹,

Gil-Zamorano²,

Hazas³

et al. 2020

Front. Genet.

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MicroRNAs (miRNAs) crucial roles in translation repression and post-transcriptional adjustments contribute to regulate intestinal lipid metabolism. Even though their actions in different metabolic tissues have been elucidated, their intestinal activity is yet unclear. We aimed to investigate intestinal miRNA-regulated lipid metabolism-related genes, by creating an intestinal-specific Dicer1 knockout (Int-Dicer1 KO) mouse model, with a depletion of microRNAs in enterocytes. The levels of 83 cholesterol and lipoprotein metabolism-related genes were assessed in the intestinal mucosa of Int-Dicer1 KO and Wild Type C57BL/6 (WT) littermates mice at baseline and 2 h after an oral lipid challenge. Among the 18 genes selected for further validation, Hmgcs2, Acat1 and Olr1 were found to be strong candidates to be modulated by miRNAs in enterocytes and intestinal organoids. Moreover, we report that intestinal miRNAs contribute to the regulation of intestinal epithelial differentiation. Twenty-nine common miRNAs found in the intestines were analyzed for their potential to target any of the three candidate genes found and validated by miRNA-transfection assays in Caco-2 cells. MiR-31-5p, miR-99b-5p, miR-200a-5p, miR-200b-5p and miR-425-5p are major regulators of these lipid metabolism-related genes. Our data provide new evidence on the potential of intestinal miRNAs as therapeutic targets in lipid metabolism-associated pathologies.

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“…ALPI is an intestinal alkaline phosphatase that is thought to function in the detoxification of lipopolysaccharide (LPS) and prevention of bacterial translocation in the gut. Mutations in ALPI abrogate the regulation of host‐microbiota interactions and restrain host inflammatory responses causing early‐onset severe diarrhea, weight loss, and severe ulcerations from transverse colon to the rectum …”

Section: Monogenic Forms Of Inflammatory Bowel Diseasementioning

confidence: 99%

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Pázmándi

Kalinichenko

Ardy

et al. 2018

Immunological Reviews

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Summary Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.

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Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Cited by 51 publications

References 43 publications

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Intestinal Lipid Metabolism Genes Regulated by miRNAs

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

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