Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene

Amorim, Marlene; Houghton, Jayne; Carmo, Sara; Salva, Inês; Pita, Ana María Simón; Pereira‐da‐Silva, Luís

doi:10.1155/2015/937201

Cited by 17 publications

(17 citation statements)

References 11 publications

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“…Almost all features described in this syndrome were present in our case. Typically, the duodenal atresia is the most common site and reported in all reported patients, but the lesion could involve any part of the gastrointestinal tract (6, 7). In our case, this anomaly was suggested by prenatal ultrasound and was confirmed and corrected surgically postnatally.…”

Section: Discussionmentioning

confidence: 99%

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Mitchell-Riley Syndrome Due to a Novel Mutation in RFX6

et al. 2019

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We report a Saudi girl who presented at birth with neonatal diabetes, duodenal atresia, and progressive cholestasis. After other gene testing was negative, the clinical diagnosis of Mitchell-Riley syndrome was ultimately considered and further genetic analysis revealed a novel missense homozygous variant in RFX6: c.983A>T (p.asp328Val). Despite intensive management, the patient died from severe Klebsiella pneumoniae sepsis at 5 months of age. This rare syndrome should be suspected in any neonate with hyperglycemia complicated by intestinal atresia and/or progressive cholestasis that could suggest biliary hypoplasia. Early recognition and diagnosis through genetic testing are essential for guiding aggressive clinical management as well as family counseling, particularly in light of the high possibility of early death in this highly complex disorder.

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Section: Discussionmentioning

confidence: 99%

“…In our case, the diagnosis of neonatal diabetes was made on the third day of her life. But the onset of diabetes could be delayed until early childhood due to residual activity of the RFX6 gene (7–11). Heterozygous RFX6 mutations appear to cause a certain form of Maturity-onset diabetes of the young (MODY) (12–15).…”

Section: Discussionmentioning

confidence: 99%

Mitchell-Riley Syndrome Due to a Novel Mutation in RFX6

et al. 2019

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“…Still, detailed Rfx6 expression and role in mouse intestine and EECs differentiation in vivo is unknown. In humans, several mutations in RFX6 were identified as the cause of an autosomal recessive syndrome, named Mitchell–Riley syndrome, characterized by neonatal or childhood diabetes comprising hepatobiliary abnormalities and intestinal atresia [22], [26], [27], [28], [29], [30], [31], [32], [33]. Most patients present with severe congenital malabsorptive diarrhea, suggesting impaired EECs differentiation; however, this has not been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells while repressing genetic programs controlling serotonin production

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et al. 2019

Molecular Metabolism

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Objective Enteroendocrine cells (EECs) of the gastro-intestinal tract sense gut luminal factors and release peptide hormones or serotonin (5-HT) to coordinate energy uptake and storage. Our goal is to decipher the gene regulatory networks controlling EECs specification from enteroendocrine progenitors. In this context, we studied the role of the transcription factor Rfx6 which had been identified as the cause of Mitchell–Riley syndrome, characterized by neonatal diabetes and congenital malabsorptive diarrhea. We previously reported that Rfx6 was essential for pancreatic beta cell development and function; however, the role of Rfx6 in EECs differentiation remained to be elucidated. Methods We examined the molecular, cellular, and metabolic consequences of constitutive and conditional deletion of Rfx6 in the embryonic and adult mouse intestine. We performed single cell and bulk RNA-Seq to characterize EECs diversity and identify Rfx6-regulated genes. Results Rfx6 is expressed in the gut endoderm; later, it is turned on in, and restricted to, enteroendocrine progenitors and persists in hormone-positive EECs. In the embryonic intestine, the constitutive lack of Rfx6 leads to gastric heterotopia, suggesting a role in the maintenance of intestinal identity. In the absence of intestinal Rfx6, EECs differentiation is severely impaired both in the embryo and adult. However, the number of serotonin-producing enterochromaffin cells and mucosal 5-HT content are increased. Concomitantly, Neurog3-positive enteroendocrine progenitors accumulate. Combined analysis of single-cell and bulk RNA-Seq data revealed that enteroendocrine progenitors differentiate in two main cell trajectories, the enterochromaffin (EC) cells and the Peptidergic Enteroendocrine (PE) cells, the differentiation programs of which are differentially regulated by Rfx6. Rfx6 operates upstream of Arx , Pax6 and Isl1 to trigger the differentiation of peptidergic EECs such as GIP-, GLP-1-, or CCK-secreting cells. On the contrary, Rfx6 represses Lmx1a and Tph1 , two genes essential for serotonin biosynthesis. Finally, we identified transcriptional changes uncovering adaptive responses to the prolonged lack of enteroendocrine hormones and leading to malabsorption and lower food efficiency ratio in Rfx6-deficient mouse intestine. Conclusion These studies identify Rfx6 as an essential transcriptional regulator of EECs specification and shed light on the molecular mechanisms of intestinal failures in human RFX6-deficiencies such as Mitchell–Riley syndrome.

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“…Lack of Rfx6 in mice blocks differentiation of all islet cell types, with the exception of pancreatic-polypeptide-producing cells, while RFX6 mutations in humans result in PNDM (93,100,128). Modeling of the RFX6 requirement for human endocrine pancreas development has been addressed by Zhu et al Their findings, in agreement with current knowledge, show a reduction of endocrine cell commitment from pancreatic progenitor cells derived from RFX6 − / − mutant hPSCs (111).…”

Section: Rfx6mentioning

confidence: 53%

Monogenic Diabetes Modeling: In Vitro Pancreatic Differentiation From Human Pluripotent Stem Cells Gains Momentum

2021

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The occurrence of diabetes mellitus is characterized by pancreatic β cell loss and chronic hyperglycemia. While Type 1 and Type 2 diabetes are the most common types, rarer forms involve mutations affecting a single gene. This characteristic has made monogenic diabetes an interesting disease group to model in vitro using human pluripotent stem cells (hPSCs). By altering the genotype of the original hPSCs or by deriving human induced pluripotent stem cells (hiPSCs) from patients with monogenic diabetes, changes in the outcome of the in vitro differentiation protocol can be analyzed in detail to infer the regulatory mechanisms affected by the disease-associated genes. This approach has been so far applied to a diversity of genes/diseases and uncovered new mechanisms. The focus of the present review is to discuss the latest findings obtained by modeling monogenic diabetes using hPSC-derived pancreatic cells generated in vitro. We will specifically focus on the interpretation of these studies, the advantages and limitations of the models used, and the future perspectives for improvement.

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Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene

Cited by 17 publications

References 11 publications

Mitchell-Riley Syndrome Due to a Novel Mutation in RFX6

Mitchell-Riley Syndrome Due to a Novel Mutation in RFX6

Rfx6 promotes the differentiation of peptide-secreting enteroendocrine cells while repressing genetic programs controlling serotonin production

Monogenic Diabetes Modeling: In Vitro Pancreatic Differentiation From Human Pluripotent Stem Cells Gains Momentum

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