Three new mutations in the hepatocyte nuclear factor-1α gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization

Yoshiuchi, Issei; Yamagata, Kazuya; Yang, Qin; Iwahashi, Hiromi; Okita, Keisuke; Yamamoto, Kenichi; Oue, Takanori; Imagawa, Akihisa; Hamaguchi, Tomoya; Yamasaki, Tomoyuki; Horikawa, Yukio; Satoh, Takeshi; Nakajima, Hitoshi; Miyazaki, Jun‐ichi; Higashiyama, Shigeki; Miyagawa, Jun Ichiro; Namba, Mitsuyoshi; Hanafusa, Toshiaki; Matsuzawa, Yūji

doi:10.1007/s001250051204

Cited by 41 publications

(43 citation statements)

References 21 publications

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“…The frameshift mutation was predicted to cause premature termination at codon 548. We also identified a conserved G to C replacement in the A site of the promoter (designated as +102G-to-C, relative to the transcription start site) which was reported previously [9]. None of these three mutations were found in the 100 control nondiabetic subjects.…”

Section: Resultssupporting

confidence: 65%

“…We identified a +102G-to-C mutation, which has been reported previously [9]. This mutation was found in a diabetic patient, who was diagnosed as having diabetes at 8 years of age and was anti-GAD-positive.…”

Section: Discussionsupporting

confidence: 53%

“…Concerning the functional properties of these mutations, the promoter activity of the +102G-to-C construct was increased by 40% and 80% compared with that of a WT-promoter construct in HepG2 and MIN6 cell, respectively [9]. The authors discussed that the +102G-to-C mutation possibly leads to increased promoter activity and thus might lead to higher than normal concentrations of HNF-1α protein and activity [9].…”

Section: Discussionmentioning

confidence: 99%

“…The authors discussed that the +102G-to-C mutation possibly leads to increased promoter activity and thus might lead to higher than normal concentrations of HNF-1α protein and activity [9].…”

Section: Discussionmentioning

confidence: 99%

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Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

et al. 2002

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Aim/hypothesis. We analysed Japanese MODY patients for mutations in the HNF-1α gene. Methods. Fifty unrelated Japanese patients with earlyonset diabetes (diagnosed at 25 years of age or younger) or with a strong family history of diabetes were screened for mutations in the HNF-1α gene. Functional studies of the mutant HNF-1α were carried out. Results. We identified three new mutations in the HNF-1α gene in the families with a strong family history for diabetes. One mutation (L518P519fsTCC→A) was identified in three unrelated families, while the other two mutations (T521I and V617I) were identified in one family. We also identified the A site of the promoter (+102G-to-C), which was reported previously. We examined the functional properties of the mutant HNF-1α. By increasing the amount of L518P519fsTCC→A-HNF-1α, increasing inhibition of the transcription of human transthyretin (TTR) was observed (up to 61% of the control). Increasing amounts of T521I-HNF-1α or V617I-HNF-1α mutant proteins increased TTR promoter transcription up to 4.3-fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4-fold of the control. Conclusion/interpretation. The L518P519fsTCC→A was identified for the first time and this mutation might be a common cause of Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations were present in two patients in the same family. Since the prevalence of these mutations is relatively high (10%, 5/50), the HNF-1α gene needs to be screened for mutations in patients either with earlyonset diabetes or with a strong family history for diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1713[Diabetologia ( -1718 Keywords MODY, HNF-1α, mutation, Japanese, gain-of-function.

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Section: Resultssupporting

confidence: 65%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

et al. 2002

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“…In contrast, HNF-1α was expressed by all four kinds of endocrine cells, so it could regulate non-beta cells as well as beta cells in the pancreas. We previously reported that glucagon secretion was also impaired along with that of insulin in a MODY3 patient [41]. Isl1 and Pax6 are known to be expressed by all kinds of endocrine cells [22,26] but exocrine cells do not express these transcription factors.…”

Section: Discussionmentioning

confidence: 98%

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

et al. 2002

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Aims/hypothesis. One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1α. The pattern of HNF-1α expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1α protein expression in the developing mouse pancreas. Methods. Double immunofluorescence staining was carried out for HNF-1α and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1α mutant mice. Results. HNF-1α was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1α was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1α was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1α on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1α. However, HNF-1α immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1α. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1α (-/-) mice, but expression was markedly decreased in the diabetic stage. Conclusion/interpretation. HNF-1α is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1α might play a role during development. [Diabetologia (2002[Diabetologia ( ) 45:1142[Diabetologia ( -1153

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Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young

Ellard

2000

Hum. Mutat.

107

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Three new mutations in the hepatocyte nuclear factor-1α gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization

Abstract: Mutations in the HNF-1alpha gene may affect the normal islet function by different molecular mechanisms.

Cited by 41 publications

References 21 publications

Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young

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