Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes

Artuso, Rosangela; Provenzano, Aldesia; Mazzinghi, Benedetta; Giunti, Laura; Palazzo, Viviana; Andreucci, Elena; Blasetti, Annalisa; Chiuri, Rosa Maria; Gianiorio, Francesco; Mandich, Paola; Monami, Matteo; Mannucci, Edoardo; Giglio, Sabrina

doi:10.1038/tpj.2014.37

Cited by 22 publications

(16 citation statements)

References 22 publications

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“…Furthermore, changes in RFX6 activity resulting from altered subcellular localization or posttranslational modifications cannot be excluded in diseased islets. Interestingly, fasting hyperglycemia has been reported in a patient bearing a heterozygote mutation in the RFX6 gene and SNP susceptibility to T2D, supporting a role for RFX6 in β cell function in humans ( Artuso et al., 2014 ).…”

Section: Discussionmentioning

confidence: 90%

Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells

et al. 2014

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SummaryIncreasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2+ channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of “disallowed” genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans.

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Section: Discussionmentioning

confidence: 90%

Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells

et al. 2014

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“…Identification of the genetic defect underlying early-onset diabetes is important for determining the specific diabetes subtype, providing personalized treatment. The study by Artuso et al [14] has revealed that NGS provides a highly sensitive method for identification of variants in a new-set of "driver genes" causing diabetes.…”

Section: Resultsmentioning

confidence: 99%

“…A breakthrough in NGS in the last decade has provided an unprecedented opportunity to investigate the contribution of genetic variation to health and disease [14]. WGS and wholeexome capture sequencing (WES) have emerged as compelling paradigms for routine clinical diagnosis, genetic risk prediction, and rare diseases [15][16][17][18].…”

Section: Genomicsmentioning

confidence: 99%

Cloud Computing for Next-Generation Sequencing Data Analysis

Zhao¹,

Watrous²,

Zhang³

et al. 2017

Cloud Computing - Architecture and Applications

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High-throughput next-generation sequencing (NGS) technologies have evolved rapidly and are reshaping the scope of genomics research. The substantial decrease in the cost of NGS techniques in the past decade has led to its rapid adoption in biological research and drug development. Genomics studies of large populations are producing a huge amount of data, giving rise to computational issues around the storage, transfer, and analysis of the data. Fortunately, cloud computing has recently emerged as a viable option to quickly and easily acquire the computational resources for large-scale NGS data analyses. Some cloud-based applications and resources have been developed specifically to address the computational challenges of working with very large volumes of data generated by NGS technology. In this chapter, we will review some cloud-based systems and solutions for NGS data analysis, discuss the practical hurdles and limitations in cloud computing, including data transfer and security, and share the lessons we learned from the implementation of Rainbow, a cloud-based tool for large-scale genome sequencing data analysis.

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“…Lastly, the mother and grandmother of the proband were treated with oral hypoglycaemic drugs for several years. In particular, the mother was treated with dipeptidyl peptidase-4 inhibitor, which was suggested to be effective for diabetes due to RFX6 mutations [10]. However, we cannot evaluate the efficacy of these drugs, because of a lack of detailed clinical data for these individuals.…”

Section: Discussionmentioning

confidence: 99%

A heterozygous protein‐truncating RFX6 variant in a family with childhood‐onset, pregnancy‐associated and adult‐onset diabetes

Akiba¹,

Ushijima

Fukami

et al. 2019

Diabet. Med.

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Background Recently, heterozygous RFX6 mutations including p.Arg377Ter were identified in individuals with maturity‐onset diabetes of the young (MODY). Clinical analysis of 36 individuals suggested that RFX6 mutation‐induced MODY is characterized by low penetrance and relatively late onset. However, given the small number of previous reports and the limited clinical information of each case, further studies are necessary to clarify the phenotypic characteristics of RFX6 mutations. Case report We identified a previously reported p.Arg377Ter variant of RFX6 in a three‐generation family with diabetes. The variant was detected through mutation screening for 30 diabetes‐associated genes. The variant was not found in public databases and was predicted to encode a truncated protein or undergo nonsense‐mediated mRNA decay. The proband showed glycosuria from 8 years of age and was diagnosed with MODY at 10 years of age, before the onset of puberty. She received basal and bolus insulin injection as initial therapy. The proband's mother exhibited glycosuria at 26 years of age when she conceived the first child. The mother was treated with insulin, oral hypoglycaemic drugs and diet. The proband and her mother were negative for islet cell autoantibodies. The maternal grandmother showed glycosuria around 50 years of age and was treated with oral hypoglycaemic drugs alone. Conclusion This study provides supporting evidence for the causal relationship between heterozygous RFX6 mutations and MODY. Furthermore, our results indicate that phenotypic consequences of RFX6 mutations are highly variable even within a single family, and possibly include childhood‐onset and pregnancy‐associated non‐autoimmune diabetes.

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Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes

Cited by 22 publications

References 22 publications

Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells

Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells

Cloud Computing for Next-Generation Sequencing Data Analysis

A heterozygous protein‐truncating RFX6 variant in a family with childhood‐onset, pregnancy‐associated and adult‐onset diabetes

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