Species-specific difference in expression and splice-site choice in Inpp5b, an inositol polyphosphate 5-phosphatase paralogous to the enzyme deficient in Lowe SyndromeReportar como inadecuado




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Mammalian Genome

, Volume 21, Issue 9–10, pp 458–466

First Online: 26 September 2010Received: 11 June 2010Accepted: 31 August 2010

Abstract

The oculocerebrorenal syndrome of Lowe OCRL; MIM #309000 is an X-linked human disorder characterized by congenital cataracts, mental retardation, and renal proximal tubular dysfunction caused by loss-of-function mutations in the OCRL gene that encodes Ocrl, a type II phosphatidylinositol bisphosphate PtdIns4,5P2 5-phosphatase. In contrast, mice with complete loss-of-function of the highly homologous ortholog Ocrl have no detectable renal, ophthalmological, or central nervous system abnormalities. We inferred that the disparate phenotype between Ocrl-deficient humans and mice was likely due to differences in how the two species compensate for loss of the Ocrl enzyme. We therefore turned our attention to Inpp5b, another type II PtdIns4,5P2 5-phosphatase encoded by Inpp5b in mice and INPP5B in humans, as potential compensating genes in the two species, because Inpp5b-INPP5B are the most highly conserved paralogs to Ocrl-OCRL in the respective genomes of both species and Inpp5b demonstrates functional overlap with Ocrl in mice in vivo. We used in silico sequence analysis, reverse-transcription PCR, quantitative PCR, and transient transfection assays of promoter function to define splice-site usage and the function of an internal promoter in mouse Inpp5b versus human INPP5B. We found mouse Inpp5b and human INPP5B differ in their transcription, splicing, and primary amino acid sequence. These observations form the foundation for analyzing the functional basis for the difference in how Inpp5b and INPP5B compensate for loss of Ocrl function and, by providing insight into the cellular roles of Ocrl and Inpp5b, aid in the development of a model system in which to study Lowe syndrome.

Electronic supplementary materialThe online version of this article doi:10.1007-s00335-010-9281-7 contains supplementary material, which is available to authorized users.

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Autor: Susan P. Bothwell - Leslie W. Farber - Adam Hoagland - Robert L. Nussbaum

Fuente: https://link.springer.com/



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