Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1β mutations

Bingham, Coralie; Ellard, Sian; Cole, Trevor; Jones, Katrin E.; Allen, Lisa; Goodship, Judith A.; Goodship, Timothy H.J.; Bakalinova-Pugh, Daniela; Russell, Ginny; Woolf, Adrian S.; Nicholls, Anthony; Hattersley, Andrew T.

doi:10.1046/j.1523-1755.2002.00272.x

Cited by 133 publications

(104 citation statements)

References 27 publications

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“…Several of the patients had additional paramesonephric duct malformations (apart from common channel anomalies), such as fusion defects of the uterus and rudimentary uterine horns. Human dominant HNF1β mutations cause the Renal Cysts and Diabetes syndrome that always features a renal malformation (including congenital solitary and horseshoe kidney, renal cystic dysplasia and glomerulocystic disease); in addition, some females have defects of paramesonephric duct differentiation (bicornuate uterus, uterus didelphys and hemi-uterus) (27)(28)(29). The human clinical genetic observations, together with the fact that HNF1β is expressed during normal development of the mammalian kidney and uterus (25,26) led us to believe that HNF1β was another excellent candidate gene to screen in patients with persistent cloaca.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we screened three other genes, Sonic Hedgehog (SHH: 7q36), Ephrin B2 (EFNB2: 13q33) and Hepatocyte Nuclear Factor 1 β(HNF1β: 17cen-q21.3). As detailed in the Discussion, SHH (8,17,(21)(22)(23), EFNB2 (24) and HNF1β (25)(26)(27)(28)(29) are expressed in the developing renal, genital and alimentary tracts, and have been functionally implicated in the normal development of these structures.…”

Section: Introductionmentioning

confidence: 99%

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Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins

Bitner‐Glindzicz

Thomasson

et al. 2007

Journal of Pediatric Urology

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Objectives-'Persistent cloaca' is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice.Patients and Methods-We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association.Results-Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation.Conclusion-Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins

Bitner‐Glindzicz

Thomasson

et al. 2007

Journal of Pediatric Urology

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“…Patients who carry the HNF1␤ mutants S151P, Q243, or R137-K161 have renal and genital tract malformations (3,6): In female patients, the uterus can be rudimentary with vaginal aplasia (Müllerian duct aplasia), or there may be a Müllerian duct fusion abnormality producing a bicornuate uterus or uterus didelphys. Potentially, genital tract malformation could also be explored in the Xenopus system.…”

Section: Discussionmentioning

confidence: 99%

“…MODY is a dominantly inherited form of non-insulin-dependent diabetes with onset usually under the age of 25 yr (2). In addition, mutated HNF1␤ alleles are associated with a variety of disorders of renal development, including solitary functioning kidney (3), renal dysplasia (3,4), glomerulocystic kidney disease (GCKD) (5), and oligomeganephronia (6). The most consistent clinical feature of the renal phenotype is renal cysts.…”

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confidence: 99%

Distinct Molecular and Morphogenetic Properties of Mutations in the Human HNF1β Gene That Lead to Defective Kidney Development

Bohn

Thomas²,

Turan³

et al. 2003

Journal of the American Society of Nephrology

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“…A wide clinical spectrum of renal morphologic and structural manifestations and functional abnormalities have been associ-ated with TCF2 mutations: Familial hypoplastic glomerulocystic kidney disease (8 -10), cystic renal dysplasia (11), solitary functioning kidney (12), oligomeganephronia (13), cystic kidneys (14), enlarged collecting systems, atypical juvenile hyperuricemic nephropathy (15), and horseshoe kidney (16,17). TCF2 adult patients have mild to moderate renal failure in the absence of diabetic nephropathy (18).…”

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confidence: 99%

Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys

Decramer

Parant

Beaufils³

et al. 2007

Journal of the American Society of Nephrology

226

194

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Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very difficult. Hepatocyte nuclear factor-1␤ that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between ؊2 and ؉2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.

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Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1β mutations

Cited by 133 publications

References 27 publications

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Distinct Molecular and Morphogenetic Properties of Mutations in the Human HNF1β Gene That Lead to Defective Kidney Development

Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys

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