HNF1ß, LHX1, and GGNBP2 deletion contributed to kidney and reproductive dysfunction in 17q12 deletion syndrome: evidence from a case report.

17q12 deletion syndrome is a chromosomal abnormality, where there is a small missing piece (deletion) of genetic material on the long arm (q) of chromosome 17. Sign and symptoms can vary widely among different patients. Recently, a patient was diagnosed with 17q12 deletion syndrome in our hospital, and the clinical characteristics presented as absence of the right kidney, compensatory hypertrophy of the left kidney, multiple small cysts in the left kidney, pancreatic atrophy, hypomagnesemia, bowed uterus, multiple follicular cysts in both lobes of the thyroid gland, and maturity-onset diabetes of the young type 5 (MODY-5). A 1.5-Mb deletion with haploinsufficiency for 20 genes within the 17q12 region was found through copy number variation (CNV) analysis based on metagenomic next-generation sequencing (mNGS) technology. In addition to HNF1B absence, the LIM-class homeobox 1 transcription factor (LHX1) and GGNBP2 absence was also involved in regulation of kidney development and the reproductive system through bioinformatics analysis. The inheriting risk of 17q12 deletion syndrome is about 50%, and it is recommended to provide genetic counseling to all patients who are suspected or diagnosed with the syndrome.

Challenges in the management of patients with HNF1B MODY and multisystem manifestations: the cases of two adolescent boys.

INTRODUCTION: Hepatocyte nuclear factor-1 beta (HNF1B) encodes a homeodomain-containing transcription factor, which is expressed early in embryogenesis and is involved in the development of multiple tissues and organs. HNF1B mutations cause complex multisystem disorders, with renal developmental disease and maturity onset diabetes of the young (HNF1B MODY), a rare cause of diabetes mellitus, being representative features. METHODS: We present two adolescent boys from different socioeconomic backgrounds who were diagnosed with genetically confirmed HNF1B MODY following hospitalization for diabetic ketoacidosis in the first case and after diagnostic work-up due to impaired glucose tolerance in the second case. Multisystem manifestations, including pancreatic hypoplasia and early-onset diabetes mellitus (DM), renal cysts, hypomagnesemia, hyperuricemia, liver and biliary impairment, genital tract malformations, and primary hyperparathyroidism were also present, strongly suggesting HNF1B MODY. RESULTS: The first patient was treated with subcutaneous insulin but was lost to follow-up due to social reasons. Conversely, early diagnosis in the second patient allowed the management of multisystem defects by a multidisciplinary team of experts. Moreover, manifestation of HNF1B MODY in the form of diabetic ketoacidosis was prevented and a structured diabetes training program has proven successful in regulating glycemic control, postponing the necessity for insulin treatment. CONCLUSION: Early genetic work-up of patients with dysglycemia associated with a specific phenotype suggestive of HNF1B MODY is extremely important in the care of children and adolescents with diabetes since it ensures that early and optimal management is initiated, thereby preventing the onset of life-threatening diabetic ketoacidosis and other multisystem complications and/or comorbidities.

A Case of 17q12 Microdeletion Syndrome in a MODY5 Type Diabetes with HNF-1ß Gene Mutation Accompanied.

Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant inherited disorder prevalent among adolescents. Typically, it manifests with hyperglycemia before the age of 25. MODY5 is attributed to a mutation in the Hepatocyte Nuclear Factor-1ß (HNF-1ß) gene. A complete absence of HNF-1ß is observed in 50% of those with MODY5. The 17q12 microdeletion syndrome closely linked with MODY5. Its incidence in the general population is around 1 in 14,500 and is linked with facial deformities, diabetes, polycystic kidneys, pancreatic hypertrophy, liver anomalies, and neuropsychological impairments. The most primary clinical signs are predominantly associated with the HNF-1ß gene deletion. We chronicle the case of a male of 19 years of age diagnosed with diabetes, who, alongside persistent liver damage and polycystic kidneys, was referred from a community hospital to the Xuzhou Central Hospital. His clinical presentation included diabetes, liver dysfunction, polycystic kidneys, lipid irregularities, insulin resistance, and fatty atrophy. Subsequent genetic screening unveiled a 17q12 chromosomal deletion and an absence of the Hepatocyte Nuclear Factor-1ß (HNF-1ß) gene. Hence, for adolescent patients lacking a familial diabetes history but exhibiting symptoms like polycystic kidneys, liver damage, lipid irregularities, and fatty atrophy, a thorough assessment for the 17q12 microdeletion syndrome becomes imperative.

1H, 13C and 15N backbone resonance assignments of hepatocyte nuclear factor-1-beta (HNF1ß) POUS and POUHD.

Hepatocyte nuclear factor 1ß (HNF1ß) is a transcription factor that plays a key role in the development and function of the liver, pancreas, and kidney. HNF1ß plays a key role in early vertebrate development and the morphogenesis of these organs. In humans, heterozygous mutations in the HNF1B gene can result in organ dysplasia, making it the most common cause of developmental renal diseases, including renal cysts, renal malformations, and familial hypoplastic glomerular cystic kidney disease. Pathogenic variants in the HNF1B gene are known to cause various diseases, including maturity-onset diabetes of the young and developmental renal diseases. This study presents the backbone resonance assignments of HNF1ß POUS and POUHD domains, which are highly conserved domains required for the recognition of double-stranded DNA. Our data will be useful for NMR studies to verify the altered structures and functions of mutant HNF1B proteins that can induce developmental renal diseases, including renal cysts, renal malformations, and familial hypoplastic glomerular cystic kidney disease. This study will provide the structural basis for future studies to elucidate the molecular mechanisms underlying how mutations in HNF1ß cause diseases.

Case Report: Diabetes mellitus type MODY5 as a feature of 17q12 deletion syndrome with diabetic gastroparesis.

Background: Maturity-onset diabetes of the young type 5 (MODY5) is an uncommon, underrecognized condition that can be encountered in several clinical contexts. It is challenging to diagnose because it is considered rare and therefore overlooked in the differential diagnosis. Moreover, no typical clinical features or routine laboratory tests can immediately inform the diagnosis. Case presentation: We report a 28-year-old man who was once misdiagnosed with type 1 diabetes due to decreased islet function and recurrent diabetic ketosis or ketoacidosis. However, he had intermittent nausea, vomiting, abdominal distension, and abdominal pain 6 months prior. Further examinations revealed agenesis of the dorsal pancreas, complex renal cyst, kidney stone, prostate cyst, hypomagnesaemia, and delayed gastric emptying. Accordingly, whole-exon gene detection was performed, and a heterozygous deletion mutation was identified at [GRCh37 (hg19)] chr17:34842526-36347106 (1.5 Mb, including HNF1B gene). The patient was eventually diagnosed with 17q12 deletion syndrome with gastroparesis. Conclusion: We report a novel case of diabetes mellitus type MODY5 as a feature of 17q12 deletion syndrome caused by a new 17q12 deletion mutation, which will further broaden the genetic mutation spectrum of this condition. With the help of gene detection technology, these findings can assist endocrinologists in making the correct diagnosis of MODY5 or 17q12 deletion syndrome. Additionally, they can formulate an appropriate therapy and conduct genetic screening counseling for their family members to guide and optimize fertility.

Pregnancy outcome with maternal HNF1B gene mutations and 17q12 deletions.

There is an increasing body of literature regarding monogenic diabetes, particularly the more common forms of glucokinase and HNF1-alpha mutations (MODY2 and MODY3). There is relatively little published literature regarding rarer mutations. HNF1-beta mutations and 17q12 deletions may be associated with a broad range of organ dysfunction, renal disease and diabetes in particular resulting in high-risk pregnancies. This manuscript describes pregnancy outcomes in a woman with an HNF1-beta mutation and 2 women with an HNF1B/17q12 deletion and reviews the previously published literature. It highlights the significant rate of adverse maternal and fetal outcomes, and the maternal features suggestive of the diagnosis which should be considered in preconception counselling.

MODY5 and Serous Ovarian Carcinoma in 17q12 Recurrent Deletion Syndrome.

Background/Objective: Maturity-onset diabetes of the young type 5 (MODY5) is caused by a hepatocyte nuclear factor 1ß (HNF1ß) gene mutation on chromosome 17q12. HNF1ß mutations have also been found in ovarian clear cell carcinoma, whereas ovarian non-clear cell carcinoma expresses this mutation rarely. 17q12 recurrent deletion syndrome features include MODY5, urogenital anomalies, and psychiatric and neurodevelopmental disorders. This is a report of a patient with 17q12 recurrent deletion syndrome with MODY5, uterine abnormalities, and low-grade serous ovarian cancer. Case Report: A 25-year-old woman with recently diagnosed stage IIIC low-grade serous ovarian carcinoma was evaluated at the endocrinology clinic for diabetes, which was diagnosed at the age of 12 years. C-peptide level was detectable and T1DM antibodies were negative. The mother had diabetes, partially septated uterus, and solitary kidney. Abdominal computed tomography showed pancreatic atrophy, ascites, omental and peritoneal nodularity, and calcifications. Laparoscopy revealed bicornuate uterus, 2 cervices, and vaginal septum. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, lymph node dissection, and omentectomy. Chromosomal microarray analysis revealed a pathogenic ∼1.8 Mb loss of 17q12, denoted arr[hg19]17q12(34477479_36283807)x1. Discussion: 17q12deletion has been described as a susceptibility locus in some ovarian cancers. However, to our knowledge, predisposition to ovarian cancer as a feature of 17q12 recurrent deletion syndrome or MODY5 was not reported previously. Conclusion: The disease association reported suggests that medical providers should periodically evaluate for ovarian cancer, gut, and urogenital abnormalities in individuals with MODY5. Likewise, individuals with diabetes plus urogenital tract abnormalities or 17q12deletion in an ovarian tumor should undergo genetic testing for MODY5.

A Case of Diabetes Mellitus Type MODY5 as a feature of 17q12 Deletion Syndrome.

Maturity onset diabetes of the young (MODY) is characterized by noninsulin-dependent diabetes diagnosed at a young age (<25 years) with an autosomal dominant inheritence. Rare mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that resemble MODY and about half of patients diagnosed with MODY5 (HNF1B mutation) have a a whole gene deletion, called as 17q12 deletion syndrome, is a rare chromosomal anomaly and is typified by deletion of the more than 15 genes including HNF1B resulting in kidney abnormalities and renal cysts and diabetes syndrome and neurodevelepmental or neuropsychiatric disorders. A 12-year-old girl was referred to our clinic, after high blood sugar was detected in the hospital where she suffered with the complaints of poliuria and polydipsia for the last 1 month. Her serum magnessium level was low (1.5 mg/dl) (normal value 1.6-2.6) and HbA1c level was 14% (normal value 3.6-5.8) and c-peptide level was 1.54 ng/ml (normal value 0.8-4). MODY5 was suspected and followed NGS gene panel (ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEURODD1, PAX4, PDX1, RFX6, ZFP57, GLIS3, FOXP3, NEUROG3, G6PC2) analysis revealed that there was no any mutation. On follow-up period, her serum magnessium level was low (1.2 mg/dl) and her urinary magnessium excretion was high at 172.5 mg/day. HNF1B gene mutation was considered in the patient with chronic hypomagnesemia with increased basal C peptide level. Abdominal CT and MR imagings revealed that there was a 43 mm diameter cystic lesion in the head of the pancreas, and agenesis of the pancreatic neck, trunk and tail as well. Because of there is no mutation in HBF1B gene in NGS panel, microarray analysis was performed, heterozygous deletion at 17q12 including HNF1B was detected. The HNF1B mutation is difficult to diagnose and has a large phenotypic variation . In case of clinical suspicion,further genetic examination (MLPA, array CGH) may be required since deletions and duplications can not be detected even if mutations in the HNF1B gene are not detected with NGS.

Case Report: A case of HNF1B mutation patient with first presentation of diabetic ketosis.

Background: Maturity-onset diabetes of the young 5 (MODY5), a rare diabetes syndrome of young adults, is associated with variants in hepatocyte nuclear factor 1B (HNF1B) gene. Case Presentation: We reported a case of MODY5, which presented with diabetic ketosis, multiple renal cysts, and hypokalemia. In this case, the HNF1B score was estimated as 13 and a heterozygous variant of HNF1B in exon 4 (c.826C>T, p.Arg276*) was identified through Sanger sequencing. Conclusions: Multiple renal cysts and youth-onset diabetes are common manifestations in patients with HNF1B mutations, and insufficient insulin secretion may be a potential cause of diabetic ketosis in MODY5.

The Clinical Characteristics and Gene Mutations of Maturity-Onset Diabetes of the Young Type 5 in Sixty-One Patients.

Aims: Maturity-onset diabetes of the young type 5 (MODY5), a rare disease, is very easy to be misdiagnosed as type 2 diabetes. To get better understanding of the disease, we analyzed the clinical characteristics and gene mutations of MODY5. Methods: PubMed, Cochrane, the China National Knowledge Infrastructure, and Wanfang were searched with the following search terms: "MODY5" OR "HNF1B maturity-onset diabetes of the young" OR "maturity-onset diabetes of the young type 5" OR "renal cysts and diabetes syndrome". Clinical characteristics and gene mutations of MODY5 were analyzed. The demography, clinical characteristics, and blood indicators of patients were described utilizing simple summary statistics. Variables were analyzed by t-test, Wilcoxon signed rank test, and Fisher exact test. Spearman's correlation analysis was used for bi-variate analysis. All tests were two-sided, and a p-value < 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for the Social Sciences version 26 for Windows (SPSS). Results: A total of 48 literatures were included in this study, including 61 eligible patients and 4 different mutations. Of the 39 patients with available body weight index, 15 (38.46%) were underweight, 21 (53.85%) were normal weight and 3 (7.69%) were overweight or obese. Of the 38 patients with available family history, 25 (65.79%) reported a family history of diabetes. Of the 34 patients with available age of diabetes diagnosis, the median age of diabetes diagnosis was 16.00 years old and 88.24% (30/34) of patients were under 25 years old when they were first diagnosed with diabetes. Renal cysts were presented in 72.41%, hypomagnesemia in 91.67%, and pancreatic dysplasia in 71.88% of the patients. Patients with hepatocyte nuclear factor 1B (HNF1B) deletion had lower serum magnesium, serum creatinine, and higher eGFR than patients with other gene mutations, and the difference was statistically significant. Conclusions: The young onset of diabetes with low or normal BMI, renal cysts, hypomagnesemia, and pancreatic dysplasia should be recommended to genetic testing in order to differentiate MODY5 from other types of diabetes earlier.

A case of familial recurrent 17q12 microdeletion syndrome presenting with severe diabetic ketoacidosis.

BACKGROUND: Heterozygous intragenic mutations of the hepatocyte nuclear factor 1 homeobox b gene (HNF1B) located on chromosome 17 and microdeletion of 17q12 region (17q12MD) leads to the complete loss of this gene, which causes renal cystic disease, diabetes mellitus (MODY5), hypomagnesemia, hyperuricemia, liver enzyme abnormalities, genital tract abnormalities and exocrine pancreatic insufficiency. In addition, patients with 17q12MD also have facial dysmorphism, neuro-developmental and neuropsychiatric disorders. CASE: A 16-year-old girl with obesity and mild facial dysmorphism was admitted to the hospital with symptoms of diabetes that started two days prior to her admission. She was diagnosed with severe diabetic ketoacidosis and treated accordingly. She had been followed up with the diagnoses of multicystic renal disease, hydronephrosis, hepatosteatosis, hypomagnesemia and hyperuricemia since the age of six. She had mild intellectual disability. Her menarche started two months ago. Cranial magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy and a partial empty sella. Her mother had diabetes, hypomagnesemia and mild intellectual disability and her maternal grandfather and uncle had diabetes. Her grandfather also had renal cystic disease. All of them are on oral antidiabetic medication. The genetic analysis of the patient and her mother revealed a loss of 1.6 megabases in chromosome 17q12. CONCLUSIONS: MODY5 should be kept in mind in patients with diabetes who present with extra pancreatic findings, especially with renal cystic disease, more over, a genetic analysis including the study of 17q12MD should be carried out in patients who present with additional neuropsychiatric findings. Ketoacidosis can be seen in patients with MODY5. Ketoacidosis and renal anomalies and dysfunction are factors that increase and affect the severity of each other in these patients.

HNF1B-MODY Masquerading as Type 1 Diabetes: A Pitfall in the Etiological Diagnosis of Diabetes.

Hepatocyte nuclear factor-1B (HNF1B) maturity-onset diabetes of the young (MODY), also referred to as "renal cysts and diabetes syndrome" or MODY-5, is a rare form of monogenic diabetes that is caused by a deletion or a point mutation in the HNF1B gene, a developmental gene that plays a key role in regulating urogenital and pancreatic development. HNF1B-MODY has been characterized by its association with renal, hepatic and other extrapancreatic features. We present the case of a 39-year-old female patient who was first diagnosed with type 1 diabetes, but then, owing to the absence of anti-islet autoantibodies and to the disease's progression, was labeled later on as having atypical type 2 diabetes. She was finally recognized as having HNF1B-MODY, a diagnosis that had been suggested by the lack of metabolic syndrome and by the presence of unexplained chronically disturbed liver function tests and hypomagnesemia. There was a 10-year delay between the onset of diabetes and the molecular diagnosis. An atypical form of diabetes, especially in patients with multisystem involvement, should raise suspicion for an alternative etiology. A timely diagnosis of HNF1B-MODY is of utmost importance since it can greatly impact diabetes management and disease progression as well as family history.

Unusual manifestations of young woman with MODY5 based on 17q12 recurrent deletion syndrome.

BACKGROUND: Maturity-onset diabetes of the young type 5 (MODY5) is a rare subtype of MODYs. It is caused by mutations of the hepatocyte nuclear factor 1 homeobox b gene (HNF1B). 17q12 recurrent deletion syndrome usually results in MODY5 because of the deletion of HNF1B. These patients often have other clinical manifestations besides diabetes. Refractory hypomagnesemia was a clue for further examination in this patient. But she lacked structural abnormalities of the genitourinary system and neurodevelopmental disorders that are common manifestations in patients with 17q12 recurrent deletion syndrome. Some atypical patients deserved attention. CASE PRESENTATION: A 21-year-old young woman was admitted to our hospital for severe malnutrition and gastrointestinal symptoms. At age 20, she was diagnosed with type 2 diabetes mellitus (T2DM) and was administered oral antidiabetic drugs. Soon afterward, the patient discontinued the medication on her own accord and then went to the hospital again due to diabetic ketoacidosis. After insulin treatment, diabetic ketoacidosis was cured and blood glucose was controlled satisfactorily. But intractable nausea, vomiting, and persistent weight loss were stubborn. Further examination revealed that the patient had hypokalemia and hard rectification hypomagnesemia. Genetic testing revealed about 1.85 Mb heterozygous fragment deletion on chromosome 17 and deletion of exons 1-9 of HNF1B heterozygosity missing was approved. Finally, the patient was diagnosed MODY5. DISCUSSION AND CONCLUSIONS: The 17q12 recurrent deletion syndrome is characterized by MODY5, structural or functional abnormalities of the kidney and urinary tract, and neurodevelopmental or neuropsychiatric disorders. This patient did not have any structural abnormalities of the genitourinary system and neuropsychiatric disorders, which is rare. She had experienced a period of misdiagnosis before being diagnosed with 17q12 recurrent deletion syndrome, and hypomagnesemia was an important clue for her diagnosis. Therefore, diabetic physicians should be alert to a special type of diabetes if patients have unexplained signs and symptoms. The absence of well-known features of HNF1B disease does not exclude MODY5.

MODY5 Hepatocyte Nuclear Factor 1ß (HNF1ß)-Associated Nephropathy: experience from a regional monogenic diabetes referral centre in Singapore.

From our monogenic diabetes registry set-up at a secondary-care diabetes center, we identified a nontrivial subpopulation (~15%) of maturity-onset diabetes of the young (MODY) among people with young-onset diabetes. In this report, we describe the diagnostic caveats, clinical features and long-term renal-trajectory of people with HNF1B mutations (HNF1B-MODY). Between 2013 and 2020, we received 267 referrals to evaluate MODY from endocrinologists in both public and private practice. Every participant was subjected to a previously reported structured evaluation process, high-throughput nucleotide sequencing and gene-dosage analysis. Out of 40 individuals with confirmed MODY, 4 (10%) had HNF1B-MODY (harboring either a HNF1B whole-gene deletion or duplication). Postsequencing follow-up biochemical and radiological evaluations revealed the known HNF1B-MODY associated systemic-features, such as transaminitis and structural renal-lesions. These anomalies could have been missed without prior knowledge of the nucleotide-sequencing results. Interestingly, preliminary longitudinal observation (up to 15 years) suggested possibly 2 distinct patterns of renal-deterioration (albuminuric vs. nonalbuminuric chronic kidney disease). Monogenic diabetes like HNF1B-MODY may be missed among young-onset diabetes in a resource-limited routine-care clinic. Collaboration with a MODY-evaluation center may fill the care-gap. The long-term renal-trajectories of HNF1B-MODY will require further studies by dedicated registries and international consortium.

Diabetes Mellitus With Renal and Müllerian Anomalies.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) type 5 is caused by an autosomal dominant mutation in the HNF1B gene. Our objective was to report a case of a young girl with bicornuate uterus and recurrent renal stones with diabetes mellitus (DM) without a family history that was diagnosed to be MODY 5. CASE REPORT: A 12-year-old girl presented with recurrent renal stones that were managed with lithotripsy and double-J stenting at various time points. At the age of 14 years, she was found to have a bicornuate uterus with an absent cervix and vagina. She was diagnosed with DM at the age of 16 years without a preceding history of osmotic symptoms or steatorrhea. Although there was no family history of young-onset diabetes, given her long-standing history of müllerian abnormalities, renal cysts, and pancreatic hypotrophy, she was evaluated for MODY. Using the next-generation sequencing, she was found to be positive for a reported HNF1B gene pathogenic mutation c.494G>A (p.Arg165His), confirming a diagnosis of MODY 5. DISCUSSION: There is a significant overlap in clinical criteria for type 2 DM and MODY in the Asian Indian population. The HNF1B gene mutation is difficult to diagnose as none of the clinical manifestations are pathognomonic and many lack a family history of DM. Diagnostic algorithms with specific clinical and biochemical criteria along with pancreatic imaging can help in case detection and direct toward particular genetic mutation analysis. CONCLUSION: We suggest that genetic testing be offered to patients with otherwise unexplained DM and such genitourinary anomalies.

A case report with functional characterization of a HNF1B mutation (p.Leu168Pro) causing MODY5.

We previously performed next-generation sequencing-based genetic screening in patients with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here,we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

Modeling HNF1B-associated monogenic diabetes using human iPSCs reveals an early stage impairment of the pancreatic developmental program.

Heterozygous mutations in HNF1B in humans result in a multisystem disorder, including pancreatic hypoplasia and diabetes mellitus. Here we used a well-controlled human induced pluripotent stem cell pancreatic differentiation model to elucidate the molecular mechanisms underlying HNF1B-associated diabetes. Our results show that lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor (FP) stage, but HNF1B haploinsufficiency allows differentiation of multipotent pancreatic progenitor cells (MPCs) and insulin-secreting ß-like cells. We show that HNF1B haploinsufficiency impairs cell proliferation in FPs and MPCs. This could be attributed to impaired induction of key pancreatic developmental genes, including SOX11, ROBO2, and additional TEAD1 target genes whose function is associated with MPC self-renewal. In this work we uncover an exhaustive list of potential HNF1B gene targets during human pancreas organogenesis whose downregulation might underlie HNF1B-associated diabetes onset in humans, thus providing an important resource to understand the pathogenesis of this disease.

A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes.

BACKGROUND: Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. CASE REPORT: A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. CONCLUSION: Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

Autosomal Dominant Tubulointerstitial Kidney Disease HNF1B With Maturity-Onset Diabetes of the Young: A Case Report With Kidney Biopsy.

Autosomal dominant tubulointerstitial kidney disease subtype hepatocyte nuclear factor 1ß (ADTKD-HNF1B) is a hereditary disease caused by variants of HNF1B that is characterized by a family history of tubulointerstitial nephropathy with concomitant diabetes mellitus. We report on a Japanese man in his early 40s who had ADTKD-HNF1B diagnosed. He had a reduced glomerular filtration rate, borderline diabetes mellitus, multiple small cysts in his bilateral kidneys, and pancreatic hypoplasia. He also had a family history of diabetes and kidney cystic lesions. These phenotypes represent ADTKD-HNF1B and genetic analysis revealed a missense variant of HNF1B. Kidney biopsy demonstrated not only tubulointerstitial fibrosis but also abnormal mitochondrial morphology in tubular cells, a novel finding.

Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review.

BACKGROUND: Diabetes mellitus with autosomal dominant inheritance, such as maturity-onset diabetes of the young (MODY), is a genetic form of diabetes mellitus. MODY is a type of monogenic diabetes mellitus in which multiple genetic variants may cause an alteration to the functioning of beta cells. The three most known forms of MODY are caused by modifications to the hnf4a, gck, and hnf1a genes. However, other MODY variants can cause multiple alterations in the embryonic development of the endoderm. This is the case in patients presenting with MODY5, who have a mutation of the hepatic nuclear factor 1B (hnf1b) gene. CASE PRESENTATION: We present the clinical case of a 15 year-old patient with a family history of diabetes mellitus and a classical MODY type 5 (MODY5) phenotype involving the pancreas and kidney, with a novel, unreported mutation in the hnf1b gene. CONCLUSIONS: MODY5 is characterised by a mutation in the hnf1b gene, which plays an important role in the development and function of multiple organs. It should be suspected in patients with unusual diabetes and multisystem involvement unrelated to diabetes.