Human adolescent nephronophthisis: Gene locus synteny with polycystic kidney disease in pcy mice

In a large Venezuelan kindred, a new type of nephronophthisis was recently identified: Adolescent nephronophthisis (NPH3) is a late-onset recessive re nal cystic disorder of the nephronophthisis/medullary cystic group of disea ses causing end-stage renal disease at a median age of 19 yr. With the use of a homozygosity mapping strategy, the gene (NPHP3) was previously localiz ed to chromosome 3q22 within a critical interval of 2.4 cM. In the current study, the NPHP3 genetic region was cloned and seven genes, eight expressed sequence-tagged sites, and seven microsatellites were physically localized within the critical disease interval. By human-mouse synteny analysis base d on expressed genes, synteny between the human NPHP3 locus on chromosome 3 q and the pcy locus on mouse chromosome 9 was clearly demonstrated, thus pr oviding the first evidence of synteny between a human and a spontaneous mur ine renal cystic disease. By fluorescence in situ hybridization the chromos omal assignment of NPHP3 to chromosome 3q21-q22 was refined. Renal patholog y in NPH3 was found to consist of tubular basement membranes changes, tubul ar atrophy and dilation, and sclerosing tubulointerstitial nephropathy. Thi s pathology clearly resembled findings observed in the recessive pcy mouse model of late-onset polycystic kidney disease. In analogy to pcy, renal cys t development at the corticomedullary junction was found to be an early sig n of the disease. Through cloning of the NPH3 critical region and mapping o f expressed genes, synteny between human NPH3 and murine pcy was establishe d, thus generating the hypothesis that both diseases are caused by recessiv e mutations of homologous genes.