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

Abstract

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 critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation

“…48 However, despite these phenotypic similarities to human disorders and the reports of genetic variation in MYSM1 in the human population (summarized in supplemental Table 6), no roles for MYSM1 in human disorders of hematopoiesis have been documented to date. MYSM1 genomic region showed association with renal hypodysplasia and diabetic retinopathy, 49,50 although similar phenotypes were not seen in the Mysm1 tm1a/tm1a mouse line. MYSM1 was also implicated in maintaining abnormal transcriptional programs in prostate cancer cell lines, and this was associated with reduced levels of H2A-K119u in prostate tumors.…”

Five cases of severe vesico-ureteric reflux in a family with an X-linked compatible trait

“…Overall, the frequency of CAKUT varies from 3 to 6 per 1,000 births [8], and VUR is included in a relevant number of them. Different modes of inheritance for VUR, isolated or associated with CAKUT, have been suggested and include autosomal dominant, polygenic and, recently, autosomal recessive traits [9][10][11][12][13]. Three loci [10,11,13] have been described that are associated with familial non-syndromic VUR, and the roundabout homolog 2 (ROBO2) gene has been identified as a disease-causing mutation in one [14].…”

Renal anomalies in families of individuals with congenital solitary kidney

“…Furthermore, it allowed identification of families in which affected relatives might have different types of renal disease, such as the previously described hereditary renal adysplasia, in which renal agenesis, hypoplasia, dysplasia, and cystic dysplasia have all been reported. [17][18][19][20] The observation that concordance for the precise type of renal anomaly was only approximately 50% among relatives suggests that many families would have been missed if the study had been limited to renal agenesis.…”

“…More recently, Roodhooft et al 15 used ultrasound to document unilateral renal agenesis and other nonlethal urogenital anomalies in a parent of 10 of 41 (24%) infants with bilateral renal agenesis or severe dysgenesis. No specific gene for hereditary renal adysplasia has been identified, although Sanna-Cherchi et al 18 recently mapped nonsyndromic renal hypodysplasia to 1p32-33.…”