Renal Phenotypes Related to Hepatocyte Nuclear Factor-1 (TCF2) Mutations in a Pediatric Cohort Tim Ulinski,* Sandra Lescure, † Sandrine Beaufils, ‡ Vincent Guigonis, † Ste ´phane Decramer, § Denis Morin,  Se ´verine Clauin, ‡ Georges Desche ˆnes,* Franc ¸ois Bouissou, § Albert Bensman,* and Christine Bellanne ´-Chantelot ¶ *Department of Pediatric Nephrology, AP-HP, Ho ˆpital Armand Trousseau, Paris, France; † Department of Pediatrics, Centre Hospitalier Universitaire, Limoges, France; Departments of ‡ Molecular Biology and ¶ Cytogenetics, AP-HP, Ho ˆpital Saint Antoine, Paris, France; § Department of Pediatrics, Centre Hospitalier Universitaire, Toulouse, France; and  Department of Pediatrics, Centre Hospitalier Universitaire, Montpellier, France The hepatocyte nuclear factor-1 encoded by the TCF2 gene plays a role for the specific regulation of gene expression in various tissues such as liver, kidney, intestine, and pancreatic islets and is involved in the embryonic development of these organs. TCF2 mutations are known to be responsible for the maturity-onset diabetes of the young type 5 associated with renal manifestations. Several observations have suggested that TCF2 mutations may be involved in restricted renal phenotypes. Eighty children (median age at diagnosis 0.2 yr) with renal cysts, hyperechogenicity, hypoplasia, or single kidneys were studied. Quantitative multiplex PCR amplification of short fluorescence fragments for the search of large genomic rearrange- ments and sequencing for the detection of point mutations were performed. TCF2 anomalies were detected in one third of patients (25 of 80). The main alteration was the complete deletion of the TCF2 gene detected in 16 patients. Family screening revealed de novo TCF2 anomalies in nine of 17 probands with a high prevalence of deletions (seven of nine). TCF2 anomalies were associated with bilateral renal anomalies (P < 0.001) and bilateral cortical cysts (P < 0.001). However, abnormal renal function, detected in 40% of patients, was independent of the TCF2 genotype. No difference in renal function or severity of renal morphologic lesions was observed between patients with a TCF2 deletion and those with point mutations. In conclusion, TCF2 molecular anomalies are involved in restricted renal phenotype in childhood without alteration of glucose metabolism. These findings have important implications in the diagnosis of patients with renal dysplasia with cysts and their follow-up. J Am Soc Nephrol 17: 497–503, 2006. doi: 10.1681/ASN.2005101040 H epatocyte nuclear factor-1 (HNF-1) is a members of the homeodomain-containing superfamily of tran- scription factors. HNF-1 functions as homodimers or heterodimers with the structurally related member HNF-1 (1). It plays a role in the tissue-specific regulation of gene expression in various organs (2), such as liver, kidney, intestine, and pancreatic islets (3). It is also greatly involved in the em- bryonic development of these organs. HNF-1 is encoded by the TCF2 gene, and heterozygous mutations in TCF2 are asso- ciated with a monogenic form of diabetes, the maturity-onset diabetes of the young type 5 (MODY5) (4). It is characterized by an autosomal dominant inheritance and nonketotic diabetes as a result of a primary defect of insulin secretion (5). Renal manifestations are systematically observed in patients with MODY5 and TCF2 mutations. They include a diverse spectrum of renal morphologic and structural manifestations such as hypoplastic glomerulocystic kidney disease (6 – 8), cys- tic renal dysplasia (9), solitary functioning kidney (10), horse- shoe kidney (11,12), and oligomeganephronia (13). Patients with TCF2 mutations have mild to moderate renal failure in the absence of diabetic nephropathy (14). Moreover, pancreatic atrophy, urogenital abnormalities, and abnormal liver enzyme levels are observed in patients with TCF2 mutations (10,13,15–17). Several observations have suggested that TCF2 mutations may be involved in restricted phenotypes, in particular, renal diseases in young patients (7,10). To address this issue, we studied 80 children who presented with structural renal abnor- malities that were detected either in utero on antenatal ultra- sound scanning or in the postnatal period. We showed that TCF2 molecular anomalies are responsible for approximately one third of renal anomalies with dysplasia and/or cysts. The mutational spectrum was characterized in two thirds of pa- tients by the identification of large genomic deletions in the TCF2 gene that mainly occurred de novo. These findings may have major clinical implications in the diagnosis and follow-up of patients with renal dysplasia. Materials and Methods Patients Eighty children (27 girls) from four pediatric departments were included over a period of 2 yr (2003 to 2004). Most of them were Received October 7, 2005. Accepted November 3, 2005. Published online ahead of print. Publication date available at www.jasn.org. Address correspondence to: Dr. Tim Ulinski, Department of Pediatric Nephrol- ogy, AP-HP, Ho ˆ pital Armand Trousseau, 26 Avenue du Docteur Netter, Paris 75571, France. Phone: +33-1-44-73-60-32; Fax: +33-1-44-73-66-63; E-mail: tim.ulinski@trs.ap-hop-paris.fr Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1702-0497