Abstract
Background
Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype–phenotype relationships remain unclear, here, we extensively studied these mutations in Japan.
Methods
We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted.
Results
Most cases had morphological abnormalities in the renal–urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091).
Conclusion
We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.
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References
Bohn S, Thomas H, Turan G, Ellard S, Bingham C, Hattersley AT, Ryffel GU. Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development. J Am Soc Nephrol. 2003;14:2033–41.
Ellard S, Bellanne-Chantelot C, Hattersley AT, European Molecular Genetics Quality Network Mg. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008;51:546–53.
Igarashi P, Shao X, McNally BT, Hiesberger T. Roles of HNF-1beta in kidney development and congenital cystic diseases. Kidney Int. 2005;68:1944–7.
Bockenhauer D, Jaureguiberry G. HNF1B-associated clinical phenotypes: the kidney and beyond. Pediatr Nephrol. 2016;31:707–14.
Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140:510–7.
El-Khairi R, Vallier L. The role of hepatocyte nuclear factor 1beta in disease and development. Diabetes Obes Metab. 2016;18(Suppl 1):23–322.
Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, Ito C, Inagaki N, Iwamoto Y, Kasuga M, Hanafusa T, Haneda M, Ueki K. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. Diabetol Int. 2010;1:2–20.
Nagano C, Nozu K, Morisada N, Yazawa M, Ichikawa D, Numasawa K, Kourakata H, Matsumura C, Tazoe S, Tanaka R, Yamamura T, Minamikawa S, Horinouchi T, Nakanishi K, Fujimura J, Sakakibara N, Nozu Y, Ye MJ, Kaito H, Iijima K. Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases. Clin Exp Nephrol. 2018;22:881–8.
Kanda S, Morisada N, Kaneko N, Yabuuchi T, Nawashiro Y, Tada N, Nishiyama K, Miyai T, Sugawara N, Ishizuka K, Chikamoto H, Akioka Y, Iijima K, Hattori M. New-onset diabetes after renal transplantation in a patient with a novel HNF1B mutation. Pediatr Transplant. 2016;20:467–71.
Faguer S, Chassaing N, Bandin F, Prouheze C, Garnier A, Casemayou A, Huart A, Schanstra JP, Calvas P, Decramer S, Chauveau D. The HNF1B score is a simple tool to select patients for HNF1B gene analysis. Kidney Int. 2014;86:1007–155.
Edghill EL, Bingham C, Ellard S, Hattersley AT. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet. 2006;43:84–90.
Madariaga L, Moriniere V, Jeanpierre C, Bouvier R, Loget P, Martinovic J, Dechelotte P, Leporrier N, Thauvin-Robinet C, Jensen UB, Gaillard D, Mathieu M, Turlin B, Attie-Bitach T, Salomon R, Gubler MC, Antignac C, Heidet L. Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin J Am Soc Nephrol. 2013;8:1179–87.
Haumaitre C, Fabre M, Cormier S, Baumann C, Delezoide AL, Cereghini S. Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Hum Mol Genet. 2006;15:2363–75.
Fischer E, Legue E, Doyen A, Nato F, Nicolas JF, Torres V, Yaniv M, Pontoglio M. Defective planar cell polarity in polycystic kidney disease. Nat Genet. 2006;38:21–3.
Gresh L, Fischer E, Reimann A, Tanguy M, Garbay S, Shao X, Hiesberger T, Fiette L, Igarashi P, Yaniv M, Pontoglio M. A transcriptional network in polycystic kidney disease. EMBO J. 2004;23:1657–68.
Heidet L, Decramer S, Pawtowski A, Moriniere V, Bandin F, Knebelmann B, Lebre AS, Faguer S, Guigonis V, Antignac C, Salomon R. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol. 2010;5:1079–90.
Dubois-Laforgue D, Cornu E, Saint-Martin C, Coste J, Bellanne-Chantelot C, Timsit J. Monogenic Diabetes Study Group of the Societe Francophone du, diabete diabetes, associated clinical spectrum, long-term prognosis, and genotype/phenotype correlations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabetes Care. 2017;40:1436–43.
Ryffel GU. Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. J Mol Endocrinol. 2001;27:11–29.
Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat Rev Nephrol. 2015;11:102–12.
Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LW, Long DA, Hennekam RC, Ledermann SE, Rees L, van't Hoff W, Marks SD, Trompeter RS, Tullus K, Winyard PJ, Cansick J, Mushtaq I, Dhillon HK, Bingham C, Edghill EL, Shroff R, Stanescu H, Ryffel GU, Ellard S, Bockenhauer D. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol. 2009;20:1123–31.
Verhave JC, Bech AP, Wetzels JF, Nijenhuis T. Hepatocyte nuclear factor 1β-associated kidney disease: more than renal cysts and diabetes. J Am Soc Nephrol. 2016;27:345–53.
Ishiwa S, Sato M, Morisada N, Nishi K, Kanamori T, Okutsu M, Ogura M, Sako M, Kosuga M, Kamei K, Ito S, Nozu K, Iijima K, Ishikura K. Association between the clinical presentation of congenital anomalies of the kidney and urinary tract (CAKUT) and gene mutations: an analysis of 66 patients at a single institution. Pediatr Nephrol. 2019. https://doi.org/10.1007/s00467-019-04230-w.
Ohara Y, Okada Y, Yamada T, Sugawara K, Kanatani M, Fukuoka H, Hirota Y, Maeda T, Morisada N, Iijima K, Ogawa W. Phenotypic differences and similarities of monozygotic twins with MODY5. J Diabetes Investig. 2019. https://doi.org/10.1111/jdi.13004 (Epub ahead of print).
Acknowledgements
The authors thank all study participants and their families. We are profoundly grateful to Mrs. Tetsuko Yamanouchi, Yoshimi Nozu, and Ming Juan Ye (Kobe University) for their technical assistance. We would like to thank Editage (https://www.editage.jp) for English language editing. Data for SC57, SC226, SC292, SC376, and SC412 patients were published elsewhere [9, 22, 23]. This work was supported by the Health Labor Sciences Research Grant for the Research on Measures for Intractable Diseases (H24-nanchi-ippan-041 to K.I.; H29-nanchi-ippan-039 to N.M.) and Japan Society for the Promotion of Science (KAKENHI Grant numbers JP15K09261 and 18K08243 to N.M.).
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K.I has received grant support from Daiichi Sankyo CO., Ltd. and Zenyaku Kogyo Co., Ltd.
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All procedures performed for studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Kobe University Graduate School of Medicine (IRB approval number 301) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Nagano, C., Morisada, N., Nozu, K. et al. Clinical characteristics of HNF1B-related disorders in a Japanese population. Clin Exp Nephrol 23, 1119–1129 (2019). https://doi.org/10.1007/s10157-019-01747-0
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DOI: https://doi.org/10.1007/s10157-019-01747-0