A novel mutation in<i>GATA6</i>causes pancreatic agenesis

Stanescu, Diana E.; Hughes, Nkecha; Patel, Puja; León, Diva D. De

doi:10.1111/pedi.12111

Cited by 30 publications

(33 citation statements)

References 12 publications

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“…The majority of GATA6 mutations in these individuals were de novo heterozygous mutations. Subsequent work confirmed this finding and revealed a more complex picture . First, patients with GATA6 mutations often present defects in other organs including the heart and gut.…”

Section: Mutations In Gata Factors and Pancreas Abnormalities In Humansmentioning

confidence: 78%

GATA factors in pancreas development and disease

2019

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There is an urgent need for the development of novel therapeutics options for diabetic patients given the high prevalence of diabetes worldwide and that, currently, there is no cure for this disease. The transplantation of pancreatic islets that contain insulin-producing cells is a promising therapeutic alternative, particularly for type 1 diabetes. However, the shortage of organ donors constitutes a major limitation for this approach; thus, developing alternative sources of insulin-producing cells is of critical importance. In the last decade, our knowledge of the molecular mechanisms controlling embryonic pancreas development has significantly advanced.More importantly, this knowledge has provided the basis for the in vitro generation of insulin-producing cells from stem cells. Recent studies have revealed that GATA transcription factors are involved in various stages of pancreas formation and in the adult ß cell function. Here, we review the fundamental role of GATA transcription factors in pancreas morphogenesis and their association with congenital diseases associated with pancreas.

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Section: Mutations In Gata Factors and Pancreas Abnormalities In Humansmentioning

confidence: 78%

GATA factors in pancreas development and disease

2019

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“…Our data demonstrating that GATA6 mutant stem cell lines could generate both pancreatic progenitors and β-like cells (Figures 4 and 5), even with decreased efficiency, was somewhat surprising as patients with GATA6 mutations often have pancreas agenesis (Stanescu et al., 2014). We identified RA signaling as an exogenous signal that may overcome the developmental block of GATA6 loss in the in vitro differentiation system.…”

Section: Discussionmentioning

confidence: 89%

GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic β Cells

et al. 2017

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SummaryInduced pluripotent stem cells were created from a pancreas agenesis patient with a mutation in GATA6. Using genome-editing technology, additional stem cell lines with mutations in both GATA6 alleles were generated and demonstrated a severe block in definitive endoderm induction, which could be rescued by re-expression of several different GATA family members. Using the endodermal progenitor stem cell culture system to bypass the developmental block at the endoderm stage, cell lines with mutations in one or both GATA6 alleles could be differentiated into β-like cells but with reduced efficiency. Use of suboptimal doses of retinoic acid during pancreas specification revealed a more severe phenotype, more closely mimicking the patient’s disease. GATA6 mutant β-like cells fail to secrete insulin upon glucose stimulation and demonstrate defective insulin processing. These data show that GATA6 plays a critical role in endoderm and pancreas specification and β-like cell functionality in humans.

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“…Similarly, although clinical PI has been reported in 81% of cases, subclinical PI and normal exocrine function have also been described (Table 3) [10, 19, 23]. Of the extra-pancreatic features, cardiac defects are the most common, in 88% of cases, although gastrointestinal, hepatobiliary, neurodevelopmental and other endocrine involvement have also been reported (Table 3) [10, 19–21, 23–29]. The family described here illustrates this clinical variability.…”

Section: Discussionmentioning

confidence: 99%

“…Summary of the pancreatic and extra-pancreatic features of the published cases to date, demonstrating the variability of the phenotype [10, 19–21, 23–29]. a NDM group includes one case of transient NDM, b childhood-onset group includes one case of impaired glucose tolerance in adolescence, c four cases were excluded as no information on exocrine insufficiency was provided, d subclinical was defined as low fecal elastase or positive fecal fat in the absence of clinical symptoms or need for pancreatic enzyme replacement…”

Section: Discussionmentioning

confidence: 99%

Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus

et al. 2017

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BackgroundHaploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of neonatal diabetes mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism.Case PresentationThe proband was born at term with severe intrauterine growth restriction, the first child of non-consanguineous parents. Diabetes occurred on day of life 1 with pancreatic exocrine insufficiency noted at several months of age. Pancreatic agenesis with absent gallbladder was confirmed when he underwent congenital diaphragmatic hernia and intestinal malrotation repair. A patent ductus arteriosus and pulmonary stenosis were repaired in infancy. Neurocognitive development has been normal. A second pregnancy was terminated due to tetralogy of Fallot and pulmonary hypoplasia secondary to congenital diaphragmatic hernia. The fetus also demonstrated severe pancreatic hypoplasia, gallbladder agenesis and intestinal rotation abnormalities. Despite severe hypoplasia, the pancreas demonstrated normal islet histology. Another sibling was found to have multiple cardiac abnormalities, requiring procedural intervention. Given the proband’s spectrum of congenital anomalies, Sanger sequencing of the GATA6 gene was performed, revealing a novel heterozygous c.635_660del frameshift mutation (p.Pro212fs). The mutation is predicted to be pathogenic, resulting in inclusion of a premature stop codon and likely degradation of the gene transcript by nonsense-mediated decay. The abortus and the sibling with the cardiac defect were both found to have the mutation, while the father and remaining sibling were negative. The mother, who is healthy with no evidence of diabetes or cardiac disease, is mosaic for the mutation at a level of 11% in her peripheral leukocytes by next-generation sequencing.ConclusionWe highlight a rare mechanism of pancreatic agenesis, this being only the second report of parental mosaicism for a GATA6 mutation and one of a handful of inherited cases. We also further define the phenotypic variability of GATA6 haploinsufficiency, even in individuals carrying the same mutation. Mutations in GATA6 should be strongly considered in cases of diabetes due to pancreatic hypoplasia or agenesis, and potentially affected family members should be tested regardless of phenotype.

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A novel mutation inGATA6causes pancreatic agenesis

Cited by 30 publications

References 12 publications

GATA factors in pancreas development and disease

GATA factors in pancreas development and disease

GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic β Cells

Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus

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