Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa

Škopková, Martina; Ciljakova, Miriam; Havlíčeková, Zuzana; Vojtková, Jarmila; Valentínová, Lucia; Daniš, Daniel; Murgaš, Dalibor; Szépeová, Renata; Staník, Juraj; Bánovčin, Peter; Klimeš, I; Gašperíková, Daniela

doi:10.1016/j.ejmg.2016.08.005

Cited by 17 publications

(29 citation statements)

References 14 publications

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“…Finally, these variants are likely to have a functional effect due to nonsense-mediated decay causing haploinsufficiency 12, 22 . This is further supported by the studies that showed that the homozygous RFX6 PTVs cause neonatal diabetes 15, 23, 24 . Among unknown MODY cases, RFX6 PTVs were responsible for 7.5% Finnish cases compared to only ~1% of non-Finnish European cases.…”

Section: Discussionmentioning

confidence: 53%

“…This reduced penetrance explains the lack of complete co-segregation in the RFX6 pedigrees. It also clarifies why diabetes was only reported in the parents or grandparents (obligate heterozygous for functional RFX6 variants) in seven out of the 12 published recessive RFX6 neonatal diabetes pedigrees 15, 18, 24, 30–36 . The lack of enrichment of RFX6 PTVs in type 2 diabetes patients compared to controls further supports their association with reduced penetrance MODY rather than type 2 diabetes.…”

Section: Discussionmentioning

confidence: 64%

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Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

et al. 2017

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Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 64%

Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

et al. 2017

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“…It has been proposed that mucosa alteration could be caused by acid secretion of the ectopic gastric tissue [30]. It is likely that gastric heterotopia is a general feature of patients with Rfx6 mutation, since anemia and melena were reported in many cases and could result from intestinal bleeding [30]. In one case, ectopic pancreatic tissue was also reported in the jejunum [30], a feature that we did not observe in Rfx6-deficient mice.…”

Section: Discussionmentioning

confidence: 58%

“…These patches of gastric heterotopia were revealed after histological analysis of intestinal resection to treat hemorrhagic ulcers. It has been proposed that mucosa alteration could be caused by acid secretion of the ectopic gastric tissue [30]. It is likely that gastric heterotopia is a general feature of patients with Rfx6 mutation, since anemia and melena were reported in many cases and could result from intestinal bleeding [30].…”

Section: Discussionmentioning

confidence: 99%

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

Piccand

Vagne

Blot

et al. 2019

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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, whose differentiation programs 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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“…To date there have been fourteen subjects identified with homozygous RFX6 mutations [106,109,110,304,305]. The majority developed diabetes as a neonate, however, four subjects were >2 years of age [305].…”

Section: Abcc8mentioning

confidence: 99%

Monogenic disorders of glucose-stimulated insulin secretion: massively parallel sequencing approaches

Johnson¹

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Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa

Cited by 17 publications

References 14 publications

Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

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

Monogenic disorders of glucose-stimulated insulin secretion: massively parallel sequencing approaches

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