Localization of a Gene for Nonsyndromic Renal Hypodysplasia to Chromosome 1p32-33

• Published in: American journal of human genetics 2007-03, Vol.80 (3), p.539-549
• Main Authors: Sanna-Cherchi, Simone, Caridi, Gianluca, Weng, Patricia L., Dagnino, Monica, Seri, Marco, Konka, Anita, Somenzi, Danio, Carrea, Alba, Izzi, Claudia, Casu, Domenica, Allegri, Landino, Schmidt-Ott, Kai M., Barasch, Jonathan, Scolari, Francesco, Ravazzolo, Roberto, Ghiggeri, Gian Marco, Gharavi, Ali G.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Child; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 1 - genetics; Classical genetics, quantitative genetics, hybrids; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genes, Dominant - physiology; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Human; Humans; Infant; Kidney - abnormalities; Kidney - pathology; Kidneys; Lod Score; Male; Malformations of the urinary system; Medical genetics; Medical sciences; Middle Aged; Molecular and cellular biology; Nephrology. Urinary tract diseases; Pedigree; Penetrance; Ureteral Diseases - genetics; Urinary tract diseases
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/512248

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure.