Clinical characteristics of HNF1B-related disorders in a Japanese population

Nagano, China; Morisada, Naoya; Nozu, Kandai; Kamei, Koichi; Tanaka, Ryojiro; Kanda, Shoichiro; Shiona, Shinichi; Araki, Yoshinori; Ohara, Shinichiro; Matsumura, Chieko; Kasahara, Katsuaki; Mori, Yoshio; Seo, Akane; Miura, Kenichiro; Washiyama, Miki; Sugimoto, Kunihisa; Harada, Ryuichi; Tazoe, Satoshi; Kourakata, H; Enseki, Mayumi; Aotani, Daisuke; Yamada, Takeshi; Sakakibara, Noburu; Yamamura, Takehira; Minamikawa, Shogo; Ishikura, Kenji; Ito, Shuichi; Hattori, Motoshi; Iijima, Kazumoto

doi:10.1007/s10157-019-01747-0

Cited by 36 publications

(47 citation statements)

References 23 publications

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“…In our study, six of the 14 patients (43%) had entire gene deletion. Similar to many other studies, all four missense mutations detected in our study were located in the DNA binding domain of the HNF1β protein [ 3 , 5 , 7 , 22 ]. HNF1B mutations are inherited in an autosomal dominant pattern and equally affect both sexes [ 23 ].…”

Section: Discussionsupporting

confidence: 90%

“…The phenotypes of HNF1B mutations are extremely variable with inter- and intrafamilial variability, and patients with HNF1B mutations typically present CAKUT, either isolated or in combination with extrarenal manifestations [ 5 , 6 , 13 , 14 ]. Cystic disease, including cystic dysplasia, is by far the most commonly identified renal phenotype in both pediatric and adult populations in most large-scale studies [ 7 , 8 , 10 , 24 ], and our study corroborated this finding (bilateral multiple renal cysts in seven patients (50%) and unilateral renal cysts with contralateral multicystic dysplastic kidney or vesicoureteral reflux in five patients (36%).…”

Section: Discussionsupporting

confidence: 86%

“…Hypokalemia and hypomagnesemia were defined as serum potassium level < 3.5 mmol/L and serum magnesium level < 1.4 mEq/L, respectively [ 13 ]. Hyperuricemia was defined as serum uric acid above 7.0 mg/dL [ 7 ]. Electrolytes abnormalities were diagnosed when abnormal levels were found repeatedly or treatment was necessary.…”

Section: Methodsmentioning

confidence: 99%

“…The kidneys are the most commonly affected organs, and renal manifestations encompass a wide spectrum of congenital abnormalities of the kidney and urinary tract (CAKUT) [ 3 , 4 , 5 ]. HNF1B mutations are the most common monogenetic cause of CAKUT and are found in 5–38% of the patients depending on the screening policy and study design [ 3 , 5 , 6 , 7 , 8 , 9 ]. Cystic kidney disease, including cystic dysplasia, is the predominant form of CAKUT associated with HNF1B mutations [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

Lim

Kim

Han

et al. 2020

JCM

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HNF1B mutations, one of the most common causes of congenital anomalies of the kidney and urinary tract, manifest as various renal and extrarenal phenotypes. We analyzed the genotype-phenotype correlations in 14 pediatric patients with HNF1B mutations. Genetic studies revealed total gene deletion in six patients (43%). All patients had bilateral renal abnormalities, primarily multiple renal cysts. Twelve patients exhibited progressive renal functional deterioration, and six of them progressed to kidney failure. The annual reduction in estimated glomerular filtration rate was−2.1 mL/min/1.73 m2. Diabetes developed in five patients (36%), including one patient with new-onset diabetes after transplantation. Neurological deficits were noted in three patients (21%), one with total gene deletion and two with missense mutations. Pancreatic abnormalities were more frequent in patients with missense mutations than in patients with other types of mutations. Genotype showed no significant correlation with renal outcomes or other extrarenal manifestations. The HNF1B scores at the times of onset and genetic diagnosis were <8 in two patients and one patient, respectively. Diagnosis of HNF1B mutations is clinically difficult because of extreme phenotypic variability and incomplete penetrance. Furthermore, some phenotypes develop with age. Therefore, patient age should be taken into consideration to increase the diagnostic rate, because some phenotypes develop with age.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

Lim

Kim

Han

et al. 2020

JCM

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“…This condition has also been associated with hypomagnesemia . Recently, Nagano et al reported that patients with HNF1B ‐related nephropathy can have hypokalemia and hypomagnesemia . Bech et al conducted a thiazide loading test on cases with HNF1B ‐related nephropathy.…”

Section: Pseudo‐bs/gsmentioning

confidence: 99%

Inherited salt‐losing tubulopathy: An old condition but a new category of tubulopathy

Nozu

Yamamura

Horinouchi

et al. 2020

Pediatrics International

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Bartter syndrome (BS) and Gitelman syndrome (GS) are syndromes associated with congenital tubular dysfunction, characterized by hypokalemia and metabolic alkalosis. Clinically, BS is classified into two types: the severe antenatal/neonatal type, which develops during the fetal period with polyhydramnios and preterm delivery; and the relatively mild classic type, which is usually found during infancy with failure to thrive. GS can be clinically differentiated from BS by its age at onset, usually after school age, or laboratory findings of hypomagnesemia and hypocalciuria. Recent advances in molecular biology have shown that these diseases can be genetically classified into type 1 to 5 BS and GS. As a result, it has become clear that the clinical classification of antenatal/neonatal BS, classic BS, and GS does not always correspond to the clinical symptoms associated with the genotypes in a one-toone manner; and there is clinically no clear differential border between type 3 BS and GS. This has caused confusion among clinicians in the diagnosis of these diseases. It has been proposed that the disease name "inherited saltlosing tubulopathy" can be used for cases of tubulopathies accompanied by hypokalemia and metabolic alkalosis. It is reasonable to use this term prior to genetic typing into type 1-5 BS or GS, to avoid confusion in a clinical setting. In this article, we review causative genes and phenotypic correlations, diagnosis, and treatment strategies for salt-losing tubulopathy as well as the clinical characteristics of pseudo-BS/GS, which can also be called a "salt-losing disorder".

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Insights into the etiology and physiopathology of MODY5 / HNF1B pancreatic phenotype with a mouse model of the human disease

et al. 2021

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Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron‐2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β‐cell volume. These defects were associated with a 30% decrease in expression of the pro‐endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar‐to‐ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Clinical characteristics of HNF1B-related disorders in a Japanese population

Cited by 36 publications

References 23 publications

Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

Inherited salt‐losing tubulopathy: An old condition but a new category of tubulopathy

Insights into the etiology and physiopathology of MODY5 / HNF1B pancreatic phenotype with a mouse model of the human disease

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