Lack of pancreatic body and tail in <i>HNF1B</i> mutation carriers

Haldorsen, Ingfrid S.; Vesterhus, Mette; Ræder, Helge; Jensen, Dag; Søvik, Oddmund; Molven, Anders; Njolstad, PR

doi:10.1111/j.1464-5491.2008.02460.x

Cited by 102 publications

(88 citation statements)

References 21 publications

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“…Indeed, lineage-tracing analyses revealed that embryonic Hnf1b + cells of the branching pancreas are precursors of acinar, duct and endocrine lineages (Solar et al, 2009). In humans, HNF1B heterozygous mutations are associated with 'maturity onset diabetes of the young type 5' (MODY5) syndrome, which is characterized by early onset of diabetes, pancreas hypoplasia and multicystic kidney dysplasia (Bellanné-Chantelot et al, 2004;Chen et al, 2010;Edghill et al, 2006;Haldorsen et al, 2008). The identification of two fetuses carrying distinct HNF1B mutations, associated with polycystic kidneys and severe pancreatic hypoplasia , further suggested an early developmental role of HNF1B in human pancreas, which might be an important cause of MODY5.…”

Section: Introductionmentioning

confidence: 99%

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

et al. 2015

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Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3 + endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5.

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Section: Introductionmentioning

confidence: 99%

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

et al. 2015

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“…A high prevalence of exocrine insufficiency has been reported in both type 1 and type 2 diabetes (4) and in HNF1A and HNF1B maturity-onset diabetes of the young (5,6). Claims that this deficiency is moderate, nonprogressive, and therefore clinically irrelevant (7) are contradicted by the finding of pathologically high fat excretion in diabetic patients with fecal elastase deficiency (4).…”

Section: Vesterhus and Associatesmentioning

confidence: 75%

Neurological Features and Enzyme Therapy in Patients With Endocrine and Exocrine Pancreas Dysfunction Due to CEL Mutations

et al. 2008

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OBJECTIVE -To further define clinical features associated with the syndrome of diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase (CEL) gene and to assess the effects of pancreatic enzyme substitution therapy.RESEARCH DESIGN AND METHODS -Nine patients with CEL gene mutation, exocrine deficiency, and diabetes were treated and followed for 30 months.RESULTS -Treatment improved symptoms in seven of nine patients. Exocrine and endocrine function assessed by fecal elastase and A1C were not affected, although fecal lipid excretion was reduced. Vitamin E was low in all patients but increased with treatment (P Ͻ 0.001 at 30 months) and improved in five subjects. A predominantly demyelinating neuropathy was seen in a majority of patients, and carpal tunnel syndrome was common.CONCLUSIONS -Pancreatic enzyme substitution alleviated symptoms and malabsorption and normalized vitamin E levels. Glycemic control was not significantly affected. The CEL syndrome seems associated with a demyelinating neuropathology.

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“…Overall 30 articles met the inclusion criteria and these reported on 53 patients; 7 children and 46 adults. The disorders associated with the 53 cases reported since 2008 are summarized in table I (5)(6)(7)(8)(9).…”

Section: Resultsmentioning

confidence: 99%

“…This anomaly was first described in 1911, and 53 cases were reported up to 2008 (3,4). Several authors have reported an association between DPA and acinar-ductal metaplasia (ADM), and neoplasia of the remnant pancreas (ventral pancreas) and diabetes (5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Agenesis of the dorsal pancreas: systematic review of a clinical challenge

Cienfuegos¹,

Rotellar²,

Salguero³

et al. 2016

Rev Esp Enferm Dig

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Background: Agenesis of the dorsal pancreas is a rare malformation. Since 1911 and until 2008, 53 cases have been reported. Several authors have recently described the association of this anomaly with neoplasia of the ventral pancreas, thus we performed a systematic review of the literature from 2008 to 2015.Methods: A systematic review of the Medline and ISI Web of Science Databases from 2008 until 2015 was carried out, and 30 articles which met the inclusion criteria were identified that included a total of 53 patients: 7 children and 46 adults.Conclusions: Although dorsal pancreatic agenesis is a rare malformation, given its association with non-alcoholic pancreatitis and neoplasia of the residual pancreas, physicians should maintain an expectant attitude.

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Lack of pancreatic body and tail in HNF1B mutation carriers

Abstract: Agenesis of the pancreatic body and tail and pancreatic exocrine dysfunction are parts of the phenotype in HNF1B mutation carriers. This strengthens the evidence for a critical role of HNF1B in development and differentiation of at least the dorsal pancreas.

Cited by 102 publications

References 21 publications

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

Neurological Features and Enzyme Therapy in Patients With Endocrine and Exocrine Pancreas Dysfunction Due to CEL Mutations

Agenesis of the dorsal pancreas: systematic review of a clinical challenge

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