Congenital Diarrhea From <i>DGAT1</i> Mutation Leading to Electrolyte Derangements, Protein‐losing Enteropathy, and Rickets

Ratchford, Thomas L; Kirby, Amelia; Pinz, Hailey; Patel, Dhiren

doi:10.1097/mpg.0000000000001750

Cited by 10 publications

(16 citation statements)

References 5 publications

(17 reference statements)

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“…Previous studies on DGAT1 deficiency have identified a total of 3 distinct homozygous and 2 compound heterozygous mutations in DGAT1. 3 , 4 , 5 , 6 These patients suffered from severe congenital diarrhea and PLE, clinical features that are shared with most of our patient cohort. Although this shared phenotype further confirms the involvement of DGAT1 in intestinal failure, limited functional data or potential therapeutic options have been reported thus far.…”

Section: Discussionmentioning

confidence: 80%

“…( B ) Exonic scheme of DGAT1 showing mutations identified in this study in black and previously identified mutations in red . 3 , 4 , 5 , 6 …”

Section: Resultsmentioning

confidence: 99%

“…Previously, mutations in the gene encoding diacylglycerol-acyltransferase 1 (DGAT1) were found to underlie a syndrome of diarrhea and congenital PLE. 3 , 4 , 5 , 6 DGAT1 and its isozyme DGAT2 (encoding for diacylglycerol-acyltransferase 2) are responsible for the conversion of diacylglycerol (DG) and fatty acyl-CoA to triacylglycerol (TG) in humans. 7 , 8 TG is the main energy substrate stored in human adipose tissue, is essential for milk production in the mammary gland, and is part of the very low-density lipoprotein–mediated transport of lipids to peripheral tissue.…”

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confidence: 99%

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Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency

et al. 2018

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Background & AimsCongenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids.MethodsWe collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7.ResultsIn the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids.ConclusionsWe identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.

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Section: Discussionmentioning

confidence: 80%

“…( B ) Exonic scheme of DGAT1 showing mutations identified in this study in black and previously identified mutations in red . 3 , 4 , 5 , 6 …”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency

et al. 2018

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“…Recent studies have shown that DGAT1 mutation is linked to chronic and severe diarrhoea that mostly develops in the neonatal period [4][5][6][7] or within 2 months after birth [7,8]. Herein, we report a female patient who had delayed-onset chronic diarrhoea with a compound heterozygous DGAT1 mutation, which, to our knowledge, has not been previously reported.…”

Section: Introductionmentioning

confidence: 78%

“…Human intestines may be more sensitive to DGAT1 mutations because of the lack of expression of DGAT2 [4]. Recent studies [4][5][6][7][8]14] (Table 1) showed mutations in DGAT1 from a total of 23 patients are linked to PLE with failure to thrive. These studies revealed that DGAT1 mutations can lead to early-onset, chronic and intractable diarrhoea, which may develop into intestinal failure.…”

Section: Discussionmentioning

confidence: 99%

DGAT1 mutations leading to delayed chronic diarrhoea: a case report

Xu¹,

Gu²,

Luo³

et al. 2020

BMC Med Genet

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Background Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. Case presentation Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. Conclusions This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

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Apoptotic enteropathy, gluten intolerance, and IBD-like inflammation associated with lipotoxicity in DGAT1 deficiency–related diarrhea: a case report of a 17-year-old patient and literature review

et al. 2022

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We present a long-term follow-up in a 17-year-old girl with DGAT1-related diarrhea, an autosomal recessive disorder characterized by impaired triglyceride absorption. Neonatal presentation included severe congenital diarrhea, protein-losing enteropathy and failure to thrive requiring total parenteral nutrition. Duodenal biopsies revealed apoptotic enteropathy and acute inflammation with the presence of macrophages and Touton giant cells, related to the intake of fat. She was able to switch to enteral nutrition on a fat-free diet. However, at age 10 she developed gluten-induced enteropathy and then IBD-like inflammation five years later. Immunohistochemistry was able to confirm the diagnosis, while DGAT1 sequencing remained inconclusive. This highlights the role of histopathology and immunohistochemistry, despite the increasing importance of genetic analysis in the diagnostic workup. This report also illustrates that parenteral nutrition weaning is possible in DGAT1-related diarrhea, but gut barrier dysfunction might increase the risk of autoimmune intestinal disease.

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Congenital Diarrhea From DGAT1 Mutation Leading to Electrolyte Derangements, Protein‐losing Enteropathy, and Rickets

Cited by 10 publications

References 5 publications

Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency

Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency

DGAT1 mutations leading to delayed chronic diarrhoea: a case report

Apoptotic enteropathy, gluten intolerance, and IBD-like inflammation associated with lipotoxicity in DGAT1 deficiency–related diarrhea: a case report of a 17-year-old patient and literature review

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