A novel <i>RFX6</i> heterozygous mutation (p.R652X) in maturity‐onset diabetes mellitus: A case report

Imaki, Sakiho; Iizuka, Katsumi; Horikawa, Yukio; Yasuda, Masakazu; Kubota, Sodai; Kato, Takehiro; Liu, Yanyan; Takao, Ken; Mizuno, Masami; Hirota, Takuo; Suwa, Tetsuya; Hosomichi, Kazuyoshi; Tajima, Atsushi; Fujiwara, Yoshihiro; Yamazaki, Y.; Kuwata, Hitoshi; Seino, Yutaka; Yabe, Daisuke

doi:10.1111/jdi.13545

Cited by 9 publications

(8 citation statements)

References 8 publications

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“…Heterozygous RFX6 pathogenic variants have been linked to MODY with reduced penetrance in humans (15)(16)(17)(18)(19)(20)(21). Moreover, genome-wide association studies (GWAS) have associated variants of RFX6 with T2D (22,23).…”

Section: Introductionmentioning

confidence: 99%

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Ibrahim,

Balboa,

Saarimäki-Vire

et al. 2023

Preprint

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Regulatory factor X 6 (RFX6) is indispensable for pancreatic endocrine development and differentiation. The RFX6 protein-truncating variant p.His293LeufsTer7 is significantly enriched in the Finnish population with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 diabetes (T2D) and gestational diabetes. To understand the role of this variant in β-cell development and function, we generated allelic series of isogenic pluripotent stem cell models and directed them into pancreatic islet lineages (SC-islets). Expectedly,in-vitromodels of the homozygousRFX6−/−variant failed to generate pancreatic endocrine cells, recapitulating the phenotype in Mitchell-Riley syndrome. Notably, heterozygousRFX6+/−derived SC-islets showed reduced β-cell maturation markers and calcium oscillations, resulting in defective insulin secretion, without affecting β-cell number or insulin content. The reduced insulin secretion is sustained duringin-vivoimplantation studies, consistent with the susceptibility of the carriers to develop diabetes.TeaserModelingRFX6-assocciated neonatal and type-2 diabetes using allelic series stem cell-derived isletsin-vitroandin-vivo.

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Section: Introductionmentioning

confidence: 99%

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Ibrahim,

Balboa,

Saarimäki-Vire

et al. 2023

Preprint

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“…Her HbA1c was 6.7% [50 mmol/mol IFCC], and her 2hr-postprandial levels of plasma glucose, serum insulin, and serum C-peptide were 140 md/dL [7.8 mM], 22.1 μU/mL [153.5 pmol/L] and 2.6 pg/mL [0.86 nmol/L], respectively. Our genetic testing for MODY-related genes [8] of the patient and her family members found a heterozygous GCK mutation (GCK: NM_000162: 10: c.1324G>T: p.E442X) in the proband (III-2), mother (II-3), and maternal grandmother (I-4); we concluded that our patient, her mother and maternal grandmother all had GCK-MODY. Consistent with other GCK-MODY cases, our patient's HbA1c was adequately controlled by healthy diet and exercise without use of anti-diabetes drugs.…”

Section: Case Presentationmentioning

confidence: 62%

“…It has been shown that hepatic GCK plays an important role in maintaining glucose homeostasis [1][2][3][4][5][6][7][8][9][10][11][12]. Pancreatic β-cell-specific disruption of the Gck gene in mice reduces by half the hyperglycemia seen in mice deficient of the Gck gene globally [11].…”

Section: Discussionmentioning

confidence: 99%

Glucokinase-maturity onset diabetes mellitus in the young suggested by factory-calibrated glucose monitoring data: a case report

Nomura

Iizuka

Goshima³

et al. 2022

Endocr J

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“…(14) Using the latest sequencing techniques, novel MODY causal genes have been recently reported in the literature such as RFX6, RFX6 protein-truncating variant (RFX6 PTV), NKX2.2, NKX6.1, WFS1, PCBD1. (7,8,9,10,11) In these rare variants no direct genotype-phenotype correlation is observed most likely due to their incomplete penetrance. (7) Information regarding the identities of these genes, their function and pathophysiology is presented in Table 1.…”

Section: A Brief Review Of Rare and Reduced-penetrant Modysmentioning

confidence: 99%

“…Recently, novel causal genes, involved in the differentiation and function of β-cells, have been detected such as RFX6, NKX2.2, NKX6.1, WFS1 and PCBD1. (7,8,9,10,11,12) This paper aims to present a rare case of the compound heterozygosity BLK/RFX6 as an underlying genetic cause of MODY. In addition, a brief review of the literature is conducted on the rare and low-penetrant MODYs, as well as on the controversies associated with this subtype of monogenic diabetes.…”

Section: Introductionmentioning

confidence: 99%

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

Hasballa,

Maggi

2023

Preprint

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Introduction: Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. Case report: The female patient at the age of 16 years old was diagnosed with non-autoimmune DM with glycated haemoglobin (HbA1c) value of 6.5%. After 6 years of dietary and lifestyle interventions due to the worsening of the glycometabolic profile, oral hypoglicemic therapy was initiated including at first only metformin, and subsequently also sulfonylureas and DPP-IV inhibitor. 11 years after diagnosis glargine insulin was started, associated 3 years later with Lispro insulin because of the worsening of the post-prandial glycaemia. According to the genetic testing a compound heterozygosis of two novel variants of uncertain/unknown clinical significance of BLK and RFX6 genes, respectively c.1013T>C (Ile338Thr) and c.1072G>A (Val358Ile), was identified. The RFX6 variant was also detected in the patient’s mother genome, while the BLK variant in her father’s. Discussion: Up to 11% of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel causal genes, involved in the differentiation and function of β-cells, have been identified such as RFX6, NKX2.2, NKX6.1, WFS1 and PCBD1. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation especially in the low-penetrant subtypes. Thus, the aim of our paper is to present additionally to such rare case of a compound heterozygosity BLK/RFX6 underlying MODY, also a brief review of literature focused on the rare and reduced-penetrant variants, as well as on some controversies regarding this subtype of monogenic diabetes. Conclusions: Due to the limited data available, the assessment of MODY related-genes pathogenicity remains challenging especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape, the genotype-phenotype correlation, as well as the pathogenetic contribution of the non-genetic modifiers in this cohort of patients.

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A novel RFX6 heterozygous mutation (p.R652X) in maturity‐onset diabetes mellitus: A case report

Cited by 9 publications

References 8 publications

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

RFX6haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Glucokinase-maturity onset diabetes mellitus in the young suggested by factory-calibrated glucose monitoring data: a case report

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

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