title: Human adolescent nephronophthisis: gene locus synteny with polycystic kidney disease in pcy mice.
abstract: In a large Venezuelan kindred, a new type of nephronophthisis was recently identified: Adolescent nephronophthisis (NPH3) is a late-onset recessive renal cystic disorder of the nephronophthisis/medullary cystic group of diseases 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 localized 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 based on expressed genes, synteny between the human NPHP3 locus on chromosome 3q and the pcy locus on mouse chromosome 9 was clearly demonstrated, thus providing the first evidence of synteny between a human and a spontaneous murine renal cystic disease. By fluorescence in situ hybridization the chromosomal assignment of NPHP3 to chromosome 3q21-q22 was refined. Renal pathology in NPH3 was found to consist of tubular basement membranes changes, tubular atrophy and dilation, and sclerosing tubulointerstitial nephropathy. This pathology clearly resembled findings observed in the recessive pcy mouse model of late-onset polycystic kidney disease. In analogy to pcy, renal cyst development at the corticomedullary junction was found to be an early sign of the disease. Through cloning of the NPH3 critical region and mapping of expressed genes, synteny between human NPH3 and murine pcy was established, thus generating the hypothesis that both diseases are caused by recessive mutations of homologous genes.
authors.affiliation: University Children's Hospital, Freiburg University, Freiburg, Germany.
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.affiliation: University Children's Hospital, Freiburg University, Freiburg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Häffner
authors.affiliation: University Children's Hospital, Freiburg University, Freiburg, Germany.
authors.forename: Suse
authors.initials: S
authors.lastname: Burth
authors.affiliation: University Hospital Los Andes, Merida, Venezuela.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez
authors.affiliation: University Hospital Los Andes, Merida, Venezuela.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Fargier
authors.affiliation: University Hospital Los Andes, Merida, Venezuela.
authors.forename: Aminta
authors.initials: A
authors.lastname: Villaquiran
authors.affiliation: University Hospital Los Andes, Merida, Venezuela.
authors.forename: Hans-Gerd
authors.initials: HG
authors.lastname: Nothwang
authors.affiliation: University Hospital Groβhadern, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: University of California, Los Angeles, California.
authors.forename: David
authors.initials: D
authors.lastname: Woo
authors.affiliation: University Children's Hospital, Freiburg University, Freiburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brandis
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Sudbrak
authors.affiliation: University Children's Hospital, Freiburg University, Freiburg, Germany.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D002648:Child; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D020161:Physical Chromosome Mapping; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000235:genetics; D013045:Species Specificity; D050396:TRPP Cation Channels
chemical_list: D011506:Proteins; D050396:TRPP Cation Channels