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      Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract

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          Abstract

          Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations, however, data are lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype-phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were 288 with vesicoureteral reflux, 120 with renal hypodysplasia and 90 with unilateral renal agenesis. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.

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          Most cited references38

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          Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.

          Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.
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            The cellular basis of kidney development.

            Mammalian kidney development has helped elucidate the general concepts of mesenchymal-epithelial interactions, inductive signaling, epithelial cell polarization, and branching morphogenesis. Through the use of genetically engineered mouse models, the manipulation of Xenopus and chick embryos, and the identification of human renal disease genes, the molecular bases for many of the early events in the developing kidney are becoming increasingly clear. Early patterning of the kidney region depends on interactions between Pax/Eya/Six genes, with essential roles for lim1 and Odd1. Ureteric bud outgrowth and branching morphogenesis are controlled by the Ret/Gdnf pathway, which is subject to positive and negative regulation by a variety of factors. A clear role for Wnt proteins in induction of the kidney mesenchyme is now well established and complements the classic literature nicely. Patterning along the proximal distal axis as the nephron develops is now being investigated and must involve aspects of Notch signaling. The development of a glomerulus requires interactions between epithelial cells and infiltrating endothelial cells to generate a unique basement membrane. The integrity of the glomerular filter depends in large part on the proteins of the nephrin complex, localized to the slit diaphragm. Despite the kidney's architectural complexity, with the advent of genomics and expression arrays, it is becoming one of the best-characterized organ systems in developmental biology.
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              FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man.

              The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and Fgf9, secreted from the adjacent ureteric bud, are necessary and sufficient to maintain progenitor stemness. Reduction in the level of these redundant ligands in the mouse led to premature progenitor differentiation within the niche. Loss of FGF20 in humans, or of both ligands in mice, resulted in kidney agenesis. Sufficiency was shown in vitro where Fgf20 or Fgf9 (alone or together with Bmp7) maintained isolated metanephric mesenchyme or sorted nephron progenitors that remained competent to differentiate in response to Wnt signals after 5 or 2 days in culture, respectively. These findings identify a long-sought-after critical component of the nephron stem cell niche and hold promise for long-term culture and utilization of these progenitors in vitro. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                0323470
                5428
                Kidney Int
                Kidney Int.
                Kidney international
                0085-2538
                1523-1755
                14 January 2014
                15 January 2014
                June 2014
                01 December 2014
                : 85
                : 6
                : 1429-1433
                Affiliations
                [1 ]Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
                [2 ]Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
                [3 ]Institute of Human Genetics, University of Bonn, Bonn, Germany
                [4 ]Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt
                [5 ]Medical Faculty, University of Belgrade, Belgrade, Serbia
                [6 ]Department of Surgery, Kuwait University, Safat, Kuwait
                [7 ]Department of Pediatric Nephrology, University Children’s Hospital, Skopje, Macedonia
                [8 ]Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
                [9 ]Department of Neonatology, Children’s Hospital, University of Bonn, Bonn, Germany
                [10 ]Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt
                [11 ]Howard Hughes Medical Institute, Chevy Chase, MD, USA
                Author notes
                Correspondence should be addressed to: Friedhelm Hildebrandt, M.D., Division of Nephrology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, Phone: +1 617-355-6129, Fax: +1 617-730-0365, friedhelm.hildebrandt@ 123456childrens.harvard.edu
                [*]

                These authors contributed equally to this work

                Article
                NIHMS543078
                10.1038/ki.2013.508
                4040148
                24429398
                5bcfd8e4-5668-47d8-9104-dd9b94fda6bc
                Categories
                Article

                Nephrology
                renal agenesis,renal development,genetic renal disease
                Nephrology
                renal agenesis, renal development, genetic renal disease

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