Abstract
Hepatocyte nuclear factor 1β (HNF1β) abnormalities have been recognized to cause congenital anomalies of the kidney and urinary tract (CAKUT), predominantly affecting bilateral renal malformations. To further understand the spectrum of HNF1β related phenotypes, we performed HNF1B gene mutation and deletion analyses in Japanese patients with renal hypodysplasia (n = 31), unilateral multicystic dysplastic kidney (MCDK; n = 14) and others (n = 5). We identified HNF1B alterations in 5 out of 50 patients (10%). De novo heterozygous complete deletions of HNF1B were found in 3 patients with unilateral MCDK. Two of the patients showed contralateral hypodysplasia, whereas the other patient showed a radiologically normal contralateral kidney with normal renal function. Copy number variation analyses showed 1.4 Mb microdeletions involving the whole HNF1B gene with breakpoints in flanking segmental duplications. We also identified 1 novel truncated mutation (1007insC) and another missense mutation (226G>T) in patients with bilateral hypodysplasia. HNF1B alterations leading to haploinsufficiency affect a diverse spectrum of CAKUT. The existence of a patient with unilateral MCDK with normal renal function might provide genetic insight into the etiology of these substantial populations of only unilateral MCDK. The recurrent microdeletions encompassing HNF1B could have a significant impact on the mechanism of HNF1B deletions.
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Pope JC 4th, Brock JW 3rd, Adams MC, Stephens FD, Ichikawa I (1999) How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J Am Soc Nephrol 10:2018–2028
Woolf AS (2000) A molecular and genetic view of human renal and urinary tract malformations. Kidney Int 58:500–512
Nakanishi K, Yoshikawa N (2003) Genetic disorders of human congenital anomalies of the kidney and urinary tract (CAKUT). Pediatr Int 45:610–616
Schedl A (2007) Renal abnormalities and their developmental origin. Nat Rev Genet 8:791–802
Cereghini S (1996) Liver-enriched transcription factors and hepatocyte differentiation. FASEB J 10:267–282
Coffinier C, Thépot D, Babinet C, Yaniv M, Barra J (1999) Essential role for the homeoprotein vHNF1/HNF1β in visceral endoderm differentiation. Development 126:4785–4794
Kolatsi-Joannou M, Bingham C, Ellard S, Bulman MP, Allen LI, Hattersley AT, Woolf AS (2001) Hepatocyte nuclear factor-1β: a new kindred with renal cysts and diabetes and gene expression in normal human development. J Am Soc Nephrol 12:2175–2180
Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI (1997) Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY. Nat Genet 17:384–385
Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, Clauin S, Deschênes G, Bouissou F, Bensman A, Bellanné-Chantelot C (2006) Renal phenotypes related to hepatocyte nuclear factor-1β (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 17:497–503
Edghill EL, Bingham C, Ellard S, Hattersley AT (2006) Mutations in hepatocyte nuclear factor-1β and their related phenotypes. J Med Genet 43:84–90
Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O (1999) A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1β. Hum Mol Genet 8:2001–2008
Weber S, Moriniere V, Knüppel T, Charbit M, Dusek J, Ghiggeri GM, Jankauskiené A, Mir S, Montini G, Peco-Antic A, Wühl E, Zurowska AM, Mehls O, Antignac C, Schaefer F, Salomon R (2006) Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol 17:2864–2870
Han BK, Babcock DS (1985) Sonographic measurements and appearance of normal kidneys in children. AJR Am J Roentgenol 145:611–616
Nozu K, Fu XJ, Nakanishi K, Yoshikawa N, Kaito H, Kanda K, Krol RP, Miyashita R, Kamitsuji H, Kanda S, Hayashi Y, Satomura K, Shimizu N, Iijima K, Matsuo M (2007) Molecular analysis of patients with type III Bartter syndrome: picking up large heterozygous deletions with semiquantitative PCR. Pediatr Res 62:364–369
Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57
Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236
De Smith AJ, Tsalenko A, Sampas N, Scheffer A, Yamada NA, Tsang P, Ben-Dor A, Yakhini Z, Ellis RJ, Bruhn L, Laderman S, Froguel P, Blakemore AI (2007) Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. Hum Mol Genet 16:2783–2794
Beards F, Frayling T, Bulman M, Horikawa Y, Allen L, Appleton M, Bell GI, Ellard S, Hattersley AT (1998) Mutations in hepatocyte nuclear factor 1β are not a common cause of maturity-onset diabetes of the young in the UK. Diabetes 47:1152–1154
Ek J, Grarup N, Urhammer SA, Gaede PH, Drivsholm T, Borch-Johnsen K, Hansen T, Pedersen O (2001) Studies of the variability of the hepatocyte nuclear factor-1β (HNF-1β / TCF2) and the dimerization cofactor of HNF-1 (DcoH / PCBD) genes in relation to type 2 diabetes mellitus and β-cell function. Hum Mutat 18:356–357
Edghill EL, Oram RA, Owens M, Stals KL, Harries LW, Hattersley AT, Ellard S, Bingham C (2008) Hepatocyte nuclear factor-1β gene deletions—a common cause of renal disease. Nephrol Dial Transplant 23:627–635
Bingham C, Hattersley AT (2004) Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1β. Nephrol Dial Transplant 19:2703–2708
Mefford HC, Clauin S, Sharp AJ, Moller RS, Ullmann R, Kapur R, Pinkel D, Cooper GM, Ventura M, Ropers HH, Tommerup N, Eichler EE, Bellanne-Chantelot C (2007) Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am J Hum Genet 81:1057–1069
Bingham C, Ellard S, Allen L, Bulman M, Shepherd M, Frayling T, Berry PJ, Clark PM, Lindner T, Bell GI, Ryffel GU, Nicholls AJ, Hattersley AT (2000) Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1β. Kidney Int 57:898–907
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 (2009) HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol 20:1123–1131
Bellanné-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noël LH, Velho G, Timsit J (2004) Clinical spectrum associated with hepatocyte nuclear factor-1β mutations. Ann Intern Med 140:510–517
Bingham C, Ellard S, Cole TR, Jones KE, Allen LI, Goodship JA, Goodship TH, Bakalinova-Pugh D, Russell GI, Woolf AS, Nicholls AJ, Hattersley AT (2002) Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1β mutations. Kidney Int 61:1243–1251
Müller D, Klopocki E, Neumann LM, Mundlos S, Taupitz M, Schulze I, Ropers HH, Querfeld U, Ullmann R (2006) A complex phenotype with cystic renal disease. Kidney Int 70:1656–1660
Kobayashi A, Kwan KM, Carroll TJ, McMahon AP, Mendelsohn CL, Behringer RR (2005) Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development 132:2809–2823
Pedersen A, Skjong C, Shawlot W (2005) Lim 1 is required for nephric duct extension and ureteric bud morphogenesis. Dev Biol 288:571–581
Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454
Takahashi N, Satoh Y, Kodaira M, Katayama H (2008) Large-scale copy number variants (CNVs) detected in different ethnic human populations. Cytogenet Genome Res 123:224–233
Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, Nibbs RJ, Freedman BI, Quinones MP, Bamshad MJ, Murthy KK, Rovin BH, Bradley W, Clark RA, Anderson SA, O’Connell RJ, Agan BK, Ahuja SS, Bologna R, Sen L, Dolan MJ, Ahuja SK (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307:1434–1440
Acknowledgements
This study was supported by a Grant in Aid for Scientific Research (B-20380240) (to K.I.) from the Japan Society for the Promotion of Science. The authors thank Ms. Yoshimi Nozu and Ms. Noriko Ito for their help with the genetic analysis.
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Nakayama, M., Nozu, K., Goto, Y. et al. HNF1B alterations associated with congenital anomalies of the kidney and urinary tract. Pediatr Nephrol 25, 1073–1079 (2010). https://doi.org/10.1007/s00467-010-1454-9
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DOI: https://doi.org/10.1007/s00467-010-1454-9