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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) account for the majority of end-stage renal disease in children (50%). Previous studies have mapped autosomal dominant loci for CAKUT. We here report a genome-wide search for linkage in a large pedigree of Somalian descent containing eight affected individuals with a non-syndromic form of CAKUT. Clinical data and blood samples were obtained from a Somalian family with eight individuals with CAKUT including high-grade vesicoureteral reflux and unilateral renal agenesis. Total genome search for linkage was performed using a 50K SNP Affymetric DNA microarray. As neither parent is affected, the results of the SNP array were analysed under recessive models of inheritance, with and without the assumption of consanguinity. Using the non-consanguineous recessive model, a new gene locus (CAKUT1) for CAKUT was mapped to chromosome 8q24 with a significant maximum parametric Logarithm of the ODDs (LOD) score (LOD(max)) of 4.2. Recombinations were observed in two patients defining a critical genetic interval of 2.5 Mb physical distance flanked by markers SNP_A-1740062 and SNP_A-1653225. We have thus identified a new non-syndromic recessive gene locus for CAKUT (CAKUT1) on chromosome 8q24. The identification of the disease-causing gene will provide further insights into the pathogenesis of urinary tract malformations and mechanisms of renal development.
    Nephrology Dialysis Transplantation 12/2009; 25(5):1496-501. · 3.37 Impact Factor
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) occur at a frequency of 1 in 500 live births and are a common cause of renal insufficiency in childhood. CAKUT encompass a wide spectrum of malformations including anomalies of the kidney, collecting system, bladder and urethra. Most cases of CAKUT are sporadic and limited to the urinary tract, but some of them are syndromic or associated with positive family history. To understand the basis of human renal anomalies, knowledge of kidney and urinary tract development is necessary. This process is very complicated, requires precise integration of a variety of progenitor cell populations of diverse embryonic origins and is controlled by many factors at every stage of development. This review focuses on the genetic factors leading to developmental errors of important morphogenetic processes, particularly in metanephric kidney induction and ureteric bud branching. The essential results of genetic studies in regard to CAKUT, performed on experimental models and in humans, are presented. However, further investigations are required to complete understanding of the complex molecular network, which will help us to determine novel preventive and therapeutic strategies for CAKUT.
    Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 01/2011; 65:829-37.
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    ABSTRACT: Primary vesicoureteric reflux (VUR), the retrograde flow of urine from the bladder toward the kidneys, results from a developmental anomaly of the vesicoureteric valve mechanism, and is often associated with other urinary tract anomalies. It is the most common urological problem in children, with an estimated prevalence of 1-2%, and is a major cause of hypertension in childhood and of renal failure in childhood or adult life. We present the results of a genetic linkage and association scan using 900,000 markers. Our linkage results show a large number of suggestive linkage peaks, with different results in two groups of families, suggesting that VUR is even more genetically heterogeneous than previously imagined. The only marker achieving P < 0.02 for linkage in both groups of families is 270 kb from EMX2. In three sibships, we found recessive linkage to KHDRBS3, previously reported in a Somali family. In another family we discovered sex-reversal associated with VUR, implicating PRKX, for which there was weak support for dominant linkage in the overall data set. Several other candidate genes are suggested by our linkage or association results, and four of our linkage peaks are within copy-number variants recently found to be associated with renal hypodysplasia. Undoubtedly there are many genes related to VUR. Our study gives support to some loci suggested by earlier studies as well as suggesting new ones, and provides numerous indications for further investigations.
    Molecular genetics & genomic medicine. 01/2014; 2(1):7-29.