title: Mouse model for Lowe syndrome/Dent Disease 2 renal tubulopathy.
abstract: The Lowe oculocerebrorenal syndrome is an X-linked disorder characterized by congenital cataracts, cognitive disability, and proximal tubular dysfunction. Both this syndrome and Dent Disease 2 result from loss-of-function mutations in the OCRL gene, which encodes a type II phosphatidylinositol bisphosphate 5-phosphatase. Ocrl-deficient mice are unaffected, however, which we believe reflects a difference in how humans and mice cope with the enzyme deficiency. Inpp5b and INPP5B, paralogous autosomal genes that encode another type II phosphoinositide 5-phosphatase in mice and humans, respectively, might explain the distinct phenotype in the two species because they are the closest paralogs to Ocrl and OCRL in their respective genomes yet differ between the two species with regard to expression and splicing. Here, we generated Ocrl(-/-) mice that express INPP5B but not Inpp5b. Similar to the human syndromes, all showed reduced postnatal growth, low molecular weight proteinuria, and aminoaciduria. Thus, we created an animal model for OCRL and Dent Disease 2 tubulopathy by humanizing a modifier paralog in mice already carrying the mutant disease gene.
authors.affiliation: University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Bothwell
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Isa M
authors.initials: IM
authors.lastname: Bernardini
authors.forename: Yien-Ming
authors.initials: YM
authors.lastname: Kuo
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
mesh_terms: D000818:Animals; D057973:Dent Disease / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D007684:Kidney Tubules / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009800:Oculocerebrorenal Syndrome / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C489581:Ocrl protein, mouse