GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes

Bonnefond, Amélie; Sand, Olivier; Guérin, Brigitte; Durand, Emmanuelle; Graeve, Franck De; Huyvaert, Marlène; Rachdi, Latif; Kerr–Conte, J.; Pattou, François; Vaxillaire, Martine; Polak, Monika; Scharfmann, Raphaël; Czernichow, P; Froguel, Philippe

doi:10.1007/s00125-012-2645-7

Cited by 55 publications

(61 citation statements)

References 9 publications

(10 reference statements)

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“…However, de novo heterozygous human GATA6 mutations, often in the DNA-binding domain, cause pancreatic agenesis [44,45]. Also important for rodent β cell generation, Gata6 is expressed in multipotent pancreatic progenitors and Gata6 −/− embryos have fewer Pdx1 + cells compared to heterozygous controls [46].…”

Section: Mpcsmentioning

confidence: 99%

Revealing transcription factors during human pancreatic β cell development

Conrad

Stein

Hunter³

2014

Trends in Endocrinology & Metabolism

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Developing cell-based diabetes therapies requires examining transcriptional mechanisms underlying human β cell development. However, increased knowledge is hampered by low availability of fetal pancreatic tissue and gene targeting strategies. Rodent models have elucidated transcription factor roles during islet organogenesis and maturation, but differences between mouse and human islets have been identified. The past 5 years have seen strides toward generating human β cell lines, the examination of human transcription factor expression, and studies utilizing induced pluripotent stem cells (iPS cells) and human embryonic stem (hES) cells to generate β-like cells. Nevertheless, much remains to be resolved. We present current knowledge of developing human β cell transcription factor expression, as compared to rodents. We also discuss recent studies employing transcription factor or epigenetic modulation to generate β cells.

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Section: Mpcsmentioning

confidence: 99%

Revealing transcription factors during human pancreatic β cell development

Conrad

Stein

Hunter³

2014

Trends in Endocrinology & Metabolism

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“…Among familial cases, variable penetrance of the diabetes phenotype has been reported regarding age of onset, severity of diabetes and exocrine insufficiency, whilst the cardiac phenotype is highly penetrant [16,22,23]. The family described here highlights the variable clinical presentation of the diabetic phenotype, with pancreatic agenesis and PNDM in the proband and hypoplasia, juvenile onset diabetes and subclinical exocrine insufficiency in the father.…”

Section: Genetic Testingmentioning

confidence: 82%

Marked intrafamilial variability of exocrine and endocrine pancreatic phenotypes due to a splice site mutation inGATA6

Savova

Franco

Shaw‐Smith

et al. 2017

Biotechnology & Biotechnological Equipment

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The objective of this study was to describe the clinical characteristics of syndromic neonatal diabetes in a family with a GATA6 mutation. A girl, currently aged 12 years 3 months, was born with intrauterine growth retardation: weight 1600 g (-4.3 SDS) at term. After birth, foramen ovale and patent ductus arteriosus (PDA) were diagnosed by echocardiography. Diabetes was diagnosed on the 9th day after birth. Exocrine pancreatic insufficiency was clinically diagnosed at about 2 years of age and pancreatic agenesis was revealed later by magnetic resonance imaging. Her father had undergone surgery during infancy for PDA and had developed insulin dependent diabetes at 12 years of age. Ultrasound revealed a thin pancreas with normal length and anatomical structure. He has subclinical exocrine pancreatic insufficiency, low insulin needs and no late complications of diabetes up to the age of 40 years. Sequencing of GATA6 identified a heterozygous splicing mutation, 1136-2A>G, in the girl and her father. Testing of the paternal grandparents showed that the mutation was likely to have arisen de novo in the father. Identification of a GATA6 mutation explains the cardiac anomalies and diabetes in this family. This case highlights the marked intrafamilial variability of both exocrine and endocrine pancreatic phenotypes in patients with GATA6 mutations.

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“…Considering other published cases, diabetes and the need for pancreatic enzyme replacement shows a wide range among individuals with different GATA6 mutations and also among family members carrying the same heterozygous GATA6 mutation [8,15,16]. To date, the mechanism how GATA6 -haploinsufficiency causes diabetes remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…In the two families studied so far, the phenotype of the exocrine pancreas and diabetes, but not of heart defects, was inconsistent in affected individuals [15,16]. This stringent role of GATA6 for heart development was underlined by many cases with only heart defects that are associated with GATA6 mutations [17,18,19].…”

Section: Introductionmentioning

confidence: 99%

Two Novel GATA6 Mutations Cause Childhood-Onset Diabetes Mellitus, Pancreas Malformation and Congenital Heart Disease

Gong

Šimaitė²,

Kühnen³

et al. 2013

Horm Res Paediatr

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Background:GATA6 mutations are the most frequent cause of pancreatic agenesis and diabetes in human sporadic cases. In families, dominantly inherited mutations show a variable phenotype also in terms of endocrine and exocrine pancreatic disease. We report two novel GATA6 mutations in an independent cohort of 8 children with pancreas aplasia or hypoplasia and diabetes. Methods: We sequenced GATA6 in 8 children with diabetes and inborn pancreas abnormalities, i.e. hypoplasia or aplasia in which other known candidate genes causing monogenic diabetes and pancreatic defects had been excluded. Results: We found two novel heterozygous GATA6 mutations (c.951_954dup and c.754_904del) in 2 patients with sporadic pancreas hypoplasia, diabetes and severe cardiac defects (common truncus arteriosus and tetralogy of Fallot), but not in the remaining 6 patients. GATA6 mutations in carriers exhibited hypoplastic pancreas with absent head in 1 patient and with increased echogenicity and decreasing exocrine function in the other patient. Additionally, hepatobiliary malformations and brain atrophy were found in 1 patient. Conclusion: Our 2 cases with novel GATA6 mutations add more phenotype characteristics of GATA6 haploinsufficiency. In agreement with an increasing number of published cases, the wide phenotypic spectrum of GATA6 diabetes syndrome should draw the attention of both pediatric endocrinologists and geneticists.

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GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes

Cited by 55 publications

References 9 publications

Revealing transcription factors during human pancreatic β cell development

Revealing transcription factors during human pancreatic β cell development

Marked intrafamilial variability of exocrine and endocrine pancreatic phenotypes due to a splice site mutation inGATA6

Two Novel GATA6 Mutations Cause Childhood-Onset Diabetes Mellitus, Pancreas Malformation and Congenital Heart Disease

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