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1.
Dev Biol ; 504: 113-119, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37739117

RESUMO

Beclin1 (Becn1) is a multifunctional protein involved in autophagy regulation, membrane trafficking, and tumor suppression. In this study, we examined the roles of Becn1 in the pancreas development by generating mice with conditional deletion of Becn1 in the pancreas using pancreatic transcriptional factor 1a (Ptf1a)-Cre mice (Becn1f/f; Ptf1aCre/+). Surprisingly, loss of Becn1 in the pancreas resulted in severe pancreatic developmental defects, leading to insufficient exocrine and endocrine pancreatic function. Approximately half of Becn1f/f; Ptf1aCre/+ mice died immediately after birth. However, duodenum and neural tissue development were almost normal, indicating that pancreatic insufficiency was the cause of death. These findings demonstrated a novel role for Becn1 in pancreas morphogenesis, differentiation, and growth, and suggested that loss of this factor leaded to pancreatic agenesis at birth.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Pâncreas , Animais , Camundongos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Duodeno/metabolismo , Pâncreas/metabolismo , Fatores de Transcrição/metabolismo
2.
Surg Radiol Anat ; 43(9): 1425-1429, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33847774

RESUMO

Left isomerism (polysplenia), one of the two major variants of heterotaxia with right isomerism (asplenia), may be rarely diagnosed in adulthood. Most cases are nevertheless asymptomatic and incidentally detected during imaging or surgery performed for unrelated conditions. We hereby report a case of left isomerism fortuitously diagnosed in a 55-year-old man with unrelated tachy-cardiomyopathy. Thoraco-abdominal computed tomography revealed a typical preduodenal portal vein (PDPV) associated with a large series of other occult anatomic variations comprising: polysplenia, agenesis of both pancreatic body and tail, complete non-rotation of the bowel and finally azygous continuation of the inferior vena cava. Subtle but highly specific thoracic features of left isomerism were also found with a bilobed right lung and bilateral long hyparterial main bronchi. The features of adult left isomerism are remembered with special attention to the PDPV.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Veia Porta/anormalidades , Tomografia Computadorizada por Raios X , Ceco/anormalidades , Humanos , Pulmão/anormalidades , Pessoa de Meia-Idade , Pâncreas/anormalidades , Baço/anormalidades
3.
BMC Med Genet ; 21(1): 70, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245430

RESUMO

BACKGROUND: Mutations in GATA6 are the most frequent cause of pancreatic agenesis. Most cases present with neonatal diabetes mellitus. CASE PRESENTATION: The case was a female born after an uncomplicated pregnancy and delivery in a non-consanguineous family (3.59 kg, 70th percentile). Severe cardiac malformations were diagnosed at two and a half months old. No hyperglycaemic episodes were recorded in the neonatal period. Diabetes was diagnosed at 21 years due to the detection of incidental glycosuria. She had a low but detectable C-peptide level at diagnosis. Anti-GAD and Islet-cell antibodies were negative and she failed oral hypoglycaemic therapy and was started on insulin. Abdominal MRI revealed the absence of most of the neck, body, and tail of pancreas with normal pancreas elastase levels. Criteria for type 1 or type 2 diabetes were not fulfilled, therefore a next generation sequencing (NGS) panel was performed. A novel heterozygous pathogenic GATA6 mutation (p.Tyr235Ter) was identified. The GATA6 variant was not detected in her parents, implying that the mutation had arisen de novo in the proband. CONCLUSION: Rarely GATA6 mutations can cause adult onset diabetes. This report highlights the importance of screening the GATA6 gene in patients with adult-onset diabetes, congenital cardiac defects and pancreatic agenesis with no first-degree family history of diabetes. It also emphasizes the importance of genetic counselling in these patients as future offspring will be at risk of inheriting the variant and developing GATA6 anomalies.


Assuntos
Anormalidades Múltiplas/genética , Diabetes Mellitus Tipo 2/genética , Fator de Transcrição GATA6/genética , Cardiopatias Congênitas/genética , Mutação , Pâncreas/anormalidades , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Cardiopatias Congênitas/complicações , Humanos , Lactente , Recém-Nascido , Transtornos de Início Tardio , Linhagem , Adulto Jovem
4.
Am J Med Genet A ; 182(6): 1496-1499, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32207556

RESUMO

GATA6 pathogenic variants primarily manifest a phenotype with pancreatic agenesis and cardiac malformations. However, additional congenital malformations affecting the biliary system, congenital diaphragmatic hernia and developmental delay have been reported. We report a newborn, prenatally diagnosed with truncus arteriosus and intrauterine growth restriction, who was postnatally found to have pancreatic agenesis associated with neonatal diabetes and hepatobiliary abnormalities. Whole exome sequencing identified a de novo, heterozygous mutation in the GATA6 gene (c.1366C>T; p.Arg456Cys). Further investigations revealed abnormalities not previously associated with GATA6 mutation, including unilateral thyroid lobe agenesis associated with congenital hypothyroidism, absent gall bladder, possible adrenal insufficiency, thrombocytopenia, and neonatal stroke.


Assuntos
Hipotireoidismo Congênito/genética , Fator de Transcrição GATA6/genética , Cardiopatias Congênitas/genética , Pâncreas/anormalidades , Pancreatopatias/congênito , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/patologia , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Pâncreas/patologia , Pancreatopatias/complicações , Pancreatopatias/genética , Pancreatopatias/patologia , Fenótipo , Sequenciamento do Exoma
5.
Clin Genet ; 93(2): 382-386, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28436541

RESUMO

Maturity-Onset Diabetes of the Young (MODY) type 4 or PDX1 -MODY is a rare form of monogenic diabetes caused by heterozygous variants in PDX1 . Pancreatic developmental anomalies related to PDX1 are reported only in neonatal diabetes cases. Here, we describe dorsal pancreatic agenesis in 2 patients with PDX1 -MODY. The proband presented with diabetes since 14 years of age and maintained regular glycemic control with low doses of basal insulin and detectable C-peptide levels after 38 years with diabetes. A diagnosis of MODY was suspected. Targeted next-generation sequencing identified a heterozygous variant in PDX1 : c.188delC/p.Pro63Argfs*60. Computed tomography revealed caudal pancreatic agenesis. Low fecal elastase indicated exocrine insufficiency. His son had impaired glucose tolerance, presented similar pancreatic agenesis, and harbored the same allelic variant. The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1 -related diabetes diagnosed after the first year of life. This finding can improve the management of MODY4 patients, leading to precocious investigation of pancreatic dysgenesis and exocrine dysfunction.


Assuntos
Anormalidades Congênitas/genética , Diabetes Mellitus Tipo 2/genética , Proteínas de Homeodomínio/genética , Pâncreas/anormalidades , Doenças Raras/genética , Transativadores/genética , Brasil , Peptídeo C/genética , Pré-Escolar , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/fisiopatologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Intolerância à Glucose/genética , Intolerância à Glucose/fisiopatologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pâncreas/fisiopatologia , Elastase Pancreática/genética , Fenótipo , Doenças Raras/diagnóstico , Doenças Raras/fisiopatologia
6.
Am J Med Genet A ; 164A(2): 476-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24310933

RESUMO

Recently, GATA6 heterozygous loss-of-function mutations were reported to cause pancreatic agenesis and congenital heart defects (PACHD [OMIM:600001]). However, the molecular mechanisms resulting from premature termination codons have not been examined in this disorder. The objective of this study was to perform a genetic analysis of a patient with PACHD. A female patient presented with ventricular septal defect, patent ductus arteriosus, and congenital diaphragmatic hernia at birth. Permanent neonatal diabetes mellitus and pancreatic exocrine deficiency due to pancreatic agenesis was diagnosed at 1 month of age. PCR-direct sequencing of GATA6 revealed that the patient is heterozygous for a novel de novo nonsense mutation of c.1477C>T, p. Arg493X in exon 5. RT-PCR direct sequencing of the RT-PCR products of total RNA from peripheral blood of the patient for the region encompassing exons 4-6 revealed only the wild-type allele. This finding provides the evidence for the occurrence of nonsense-mediated mRNA decay (NMD) in the p.Arg493X mutation. Quantitative RT-PCR analysis revealed that the expression of GATA6 transcript in the patient was less than half compared with normal control samples. This is the first evidence that GATA6 haploinsufficiency is caused by NMD in vivo, and we conclude that GATA6 haploinsufficiency causes not only PACHD but may affect other organs derived from the endoderm. Further screenings of GATA6 mutations in patients with various forms of diabetes and/or congenital heart disease with other visceral malformation may reveal the impact of GATA6 mutations on diabetes and congenital malformation.


Assuntos
Códon sem Sentido , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Fator de Transcrição GATA6/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Pâncreas/anormalidades , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Expressão Gênica , Haploinsuficiência , Heterozigoto , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , RNA Mensageiro/genética , Tomografia Computadorizada por Raios X
7.
Cureus ; 15(10): e47202, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37854477

RESUMO

Background Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. It is often related to genetic mutations; hence, genetic testing is warranted. Here, we present six cases of pancreatic agenesis resulting in neonatal diabetes with PTF1A gene mutation. Methodology This retrospective case series study included six pediatric cases of neonatal diabetes mellitus who are currently following at pediatric endocrinology clinics at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Results The study reported six patients with a mean age of eight years who presented with pancreatic agenesis resulting in neonatal diabetes with PTF1A gene mutation. In four patients, there was no evidence of cerebellar agenesis. Conclusions Neonatal diabetes is a challenging disease that must be diagnosed early to prevent subsequent metabolic complications. Genetic testing is recommended in neonates who present with prolonged duration of hyperglycemia. Insulin replacement is the treatment of choice.

8.
J Neonatal Perinatal Med ; 13(4): 543-553, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32333556

RESUMO

BACKGROUND: Precision medicine, described as a therapeutic procedure in which complex diseases are treated based on the causal gene and pathophysiology, is being considered for diabetes mellitus (DM). To this end, several monogenetic mutations in the beta cells have been linked with neonatal diabetes mellitus (NDM), however, the list of suspect genes is expansive, necessitating an update. This study, therefore, provides an update on NDM candidate genes and pathophysiology. RESULTS: Reputable online academic databases were searched for relevant information, which led to the identification of 43 genes whose mutations are linked to the condition. Of the linked genes, mutations in the KCNJ11, ABCC8, and INS genes as well as the genes on 6q24 chromosomal region are the most frequently implicated. Mutations in these genes can cause pancreatic agenesis and developmental errors, resulting in NDM in the first six to twelve months of birth. The clinical presentations of NDM include frequent urination, rapid breathing, and dehydration, among others. CONCLUSIONS: Monogenetic mutations in the beta cells may cause NDM with distinct pathophysiology from other DM. Treatment options that target NDM candidate genes and pathophysiology may lead to an improved treatment compared with the present generalized treatment for all forms of DM.


Assuntos
Diabetes Mellitus , Estudos de Associação Genética , Doenças do Recém-Nascido , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/terapia , Humanos , Recém-Nascido , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/fisiopatologia , Doenças do Recém-Nascido/terapia , Medicina de Precisão/métodos
9.
Cell Stem Cell ; 27(1): 137-146.e6, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32442395

RESUMO

GATA6 is a critical regulator of pancreatic development, with heterozygous mutations in this transcription factor being the most common cause of pancreatic agenesis. To study the variability in disease phenotype among individuals harboring these mutations, a patient-induced pluripotent stem cell model was used. Interestingly, GATA6 protein expression remained depressed in pancreatic progenitor cells even after correction of the coding mutation. Screening the regulatory regions of the GATA6 gene in these patient cells and 32 additional agenesis patients revealed a higher minor allele frequency of a SNP 3' of the GATA6 coding sequence. Introduction of this minor allele SNP by genome editing confirmed its functionality in depressing GATA6 expression and the efficiency of pancreas differentiation. This work highlights a possible genetic modifier contributing to pancreatic agenesis and demonstrates the usefulness of using patient-induced pluripotent stem cells for targeted discovery and validation of non-coding gene variants affecting gene expression and disease penetrance.


Assuntos
Células-Tronco Pluripotentes Induzidas , Diferenciação Celular/genética , Fator de Transcrição GATA6/genética , Humanos , Organogênese , Pâncreas
10.
Radiol Case Rep ; 14(1): 79-82, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30377453

RESUMO

Agenesis of the dorsal pancreas (ADP) is an extremely rare congenital anomaly. Human pancreas is formed by ventral and dorsal endodermal buds of the foregut endoderm. The dorsal bud forms the upper part of the head, neck, body, and tail of the pancreas and the ventral bud generates most of the head and uncinate process. ADP is derived from the embryologic failure of the dorsal pancreatic bud to form the pancreatic body and tail. ADP can be related to some diseases and conditions such as pancreatitis, hypoglycemia, and rarely pancreatic tumors. The association between cystic lesions with ADP has previously been reported. Three cases of cystic lesions of the pancreas with ADP were diagnosed clinically based on the imaging features and without any past history of pancreatitis. However, the pathologic diagnosis of resected lesions confirmed pseudocysts without pathologic evidence of tumor. We report 3 cases of pancreatic pseudocysts associated with ADP.

11.
Stem Cell Reports ; 12(1): 57-70, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30629940

RESUMO

Heterozygous de novo mutations in GATA6 are the most frequent cause of pancreatic agenesis in humans. In mice, however, a similar phenotype requires the biallelic loss of Gata6 and its paralog Gata4. To elaborate the human-specific requirements for GATA6, we chose to model GATA6 loss in vitro by combining both gene-edited and patient-derived pluripotent stem cells (hPSCs) and directed differentiation toward ß-like cells. We find that GATA6 heterozygous hPSCs show a modest reduction in definitive endoderm (DE) formation, while GATA6-null hPSCs fail to enter the DE lineage. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes. The early deficit in DE is accompanied by a significant reduction in PDX1+ pancreatic progenitors and C-PEPTIDE+ ß-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.


Assuntos
Diferenciação Celular , Endoderma/metabolismo , Fator de Transcrição GATA6/genética , Redes Reguladoras de Genes , Células Secretoras de Insulina/metabolismo , Pâncreas/anormalidades , Pancreatopatias/congênito , Células-Tronco Pluripotentes/metabolismo , Linhagem da Célula , Células Cultivadas , Endoderma/citologia , Fator de Transcrição GATA6/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/citologia , Pâncreas/metabolismo , Pancreatopatias/genética , Pancreatopatias/metabolismo , Células-Tronco Pluripotentes/citologia , Ligação Proteica , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Transativadores/genética , Transativadores/metabolismo
12.
Mol Genet Genomic Med ; 7(10): e00753, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441606

RESUMO

BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta- cell development, and are either involved in beta-cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics. METHODS: To calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16-year-period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort. RESULTS: PNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B. CONCLUSION: Qatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature.


Assuntos
Diabetes Mellitus/diagnóstico , Glicemia/análise , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Elementos Facilitadores Genéticos , Epífises/anormalidades , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/genética , Feminino , Deleção de Genes , Quinases do Centro Germinativo/genética , Transportador de Glucose Tipo 2/genética , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Catar , Fatores de Transcrição/genética , Sequenciamento Completo do Genoma
13.
Radiol Case Rep ; 13(1): 68-71, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29487639

RESUMO

Dorsal pancreatic agenesis is a very rare congenital anomaly. Unilateral renal agenesis, on the other hand, is a relatively common congenital anomaly, although its etiology is not fully understood. Renal and pancreatic embryologic development appears to be nonrelated. We report a case of a 34-year-old man who was referred to our hospital for evaluation of cholestasis and microalbuminuria. Ultrasound and magnetic resonance imaging examinations showed empty right renal fossa and absence of the pancreatic neck, body, and tail. Our case report is the second case of a dorsal pancreatic agenesis and unilateral renal agenesis in a young male patient.

14.
BMJ Case Rep ; 20182018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29444795

RESUMO

Dorsal pancreatic agenesis is an extremely rare entity characterised by absence of body and tail of pancreas, while there are so many other developmental anomalies of the pancreas that have been reported. Here we report a 25-year-old young man who presented with pain in the abdomen, recurrent loose stools and hyperglycaemia. On radiological imaging study, there was complete agenesis of the dorsal pancreas except for thin stripe of tissue at the level of the uncinate process. Both exocrinedysfunction and endocrine dysfunction were present in this patient. Patient was supplemented with pancreatic enzyme preparation and insulin.


Assuntos
Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/tratamento farmacológico , Insulina/uso terapêutico , Pâncreas/anormalidades , Extratos Pancreáticos/uso terapêutico , Adulto , Colangiopancreatografia por Ressonância Magnética , Anormalidades Congênitas/patologia , Diabetes Mellitus Tipo 1/etiologia , Diagnóstico Diferencial , Humanos , Masculino , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Doenças Raras/complicações , Doenças Raras/diagnóstico por imagem , Tomografia Computadorizada por Raios X
15.
J Clin Res Pediatr Endocrinol ; 9(3): 274-277, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28663161

RESUMO

Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: A frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis.


Assuntos
Hiperglicemia/genética , Pâncreas/anormalidades , Fatores de Transcrição/genética , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido , Masculino , Mutação
16.
Stem Cell Reports ; 8(3): 589-604, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28196690

RESUMO

Induced 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 ß-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 ß-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 ß-like cell functionality in humans.


Assuntos
Endoderma/metabolismo , Fator de Transcrição GATA6/genética , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Endoderma/efeitos dos fármacos , Endoderma/embriologia , Fator de Transcrição GATA6/metabolismo , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Modelos Biológicos , Família Multigênica , Mutação , Pâncreas/embriologia , Fenótipo , Tretinoína/farmacologia
17.
Cell Stem Cell ; 20(5): 675-688.e6, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28196600

RESUMO

Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6.1+ stage, leading to impaired formation of glucose-responsive ß-like cells. In addition to this GATA6 haploinsufficiency, we also identified dosage-sensitive requirements for GATA6 and GATA4 in the formation of both definitive endoderm and pancreatic progenitor cells. Our work expands the application of hPSCs from studying the impact of individual gene loci to investigation of multigenic human traits, and it establishes an approach for identifying genetic modifiers of human disease.


Assuntos
Fator de Transcrição GATA4/genética , Fator de Transcrição GATA6/genética , Edição de Genes/métodos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular , Imunofluorescência , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Humanos , Masculino , Pâncreas/citologia , Pâncreas/metabolismo
18.
Int J Surg Case Rep ; 6C: 169-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25544484

RESUMO

CONTEXT: Agenesis of the dorsal pancreas is a rare anomaly, mostly associated with other medical conditions. It may be complicated with pancreatic neoplasms. CASE REPORT: We report the case of a 51-year-old male with selective agenesis of pancreatic isthmus with preservation of main pancreatic duct and branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) with suspicious features of the pancreas. CONCLUSION: This is probably the first report of isolated agenesis of pancreatic isthmus with conservation of main pancreatic duct.

19.
Indian J Radiol Imaging ; 24(2): 156-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25024525

RESUMO

The morphogenesis of the pancreas is a complex process having a very low frequency of anatomic variation. The congenital anomalies are rare. Complete pancreatic and ventral pancreatic agenesis are incompatible with life. Dorsal pancreatic agenesis is exceedingly rare with less than 100 cases reported in the world literature. Patients with this anomaly may be asymptomatic or may present with abdominal pain, hyperglycemia, diabetes mellitus, and acute or chronic pancreatitis. Such anomalies are rarely reported; therefore, clinical awareness of agenesis of the dorsal pancreas as a cause of these symptoms can expand the differential diagnosis and improve patient management.

20.
Indian J Surg ; 76(2): 137-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24891779

RESUMO

Preduodenal portal vein (PDPV) is a rare developmental anomaly. In infants, this is often associated with duodenal obstruction or biliary atresia. It is generally asymptomatic in adults (Ooshima et al., Hepato-Biliary-Pancreat Surg 5(4):455-458, 1998). Here, we report a singular case of adult PDPV that was discovered accidentally during emergency laparotomy for peritonitis due to gastric perforation in a 38-year-old lady. A plethora of congenital anomalies was uncovered, which is consistent with the reported cases of classical polysplenia syndrome, viz., multiple spleens of equal volume, visceral heterotaxia, right (Rt.)-sided stomach, a left (Lt.)-sided or a large midline liver, malrotation of intestine, a short pancreas, PDPV and IVC abnormalities (Gayer et al., Abdom Imaging 24:178-184, 1999). In addition, abnormalities like anamolous origin of Lt. gastric and splenic arteries from the abdominal aorta with absent celiac trunk, hepatic artery arising from the superior mesenteric artery, hepatic veins draining directly to Rt. atrium, etc. along with hypertrophic and lipomatous interatrial septum have also been detected during further investigations. As of now, we have come across 29 cases of adult PDPV reported in world literature and we are reporting our unique case with a review of literature on anomalies of visceral organs associated with PDPV.

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