Localization of a gene for nonsyndromic renal hypodysplasia to chromosome 1p32-33.

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

The Paternal-Age Effect in Apert Syndrome Is Due, in Part, to the Increased Frequency of Mutations in Sperm

t of men ascertained because they had a child with AS. No age-related increase in the frequency of these mutations was observed in leukocytes. Selection and/or quality-control mechanisms, including DNA repair and apoptosis, may contribute to the cell-type differences in mutation frequency. Much has been written about the "mutagenic male" (Hurst and Ellegren 2002) and the higher male-to-female mutation rate in many genetic disorders (Vogel and Rathenberg 1975; Crow 2000). Conventional wisdom says that the greater number of germ-cell divisions in males compared with females contributes to the higher mutation frequency in males (Penrose 1955), which manifests as an increased incidence with paternal age of de novo cases of disorders, as well as paternally derived mutations (Moloney et al. 1996; Shuffenecker et al. 1997; Wilkin et al. 1998; Glaser et al. 2000). However, the linear increase with age in the number of divisions does not fully explain the exponential increase with paternal ag