A Mouse with an N-Ethyl-N-Nitrosourea (ENU) Induced Trp589Arg Galnt3 Mutation Represents a Model for Hyperphosphataemic Familial Tumoural Calcinosis

Esapa, Christopher T., Head, Rosie A., Jeyabalan, Jeshmi, Evans, Holly, Hough, Tertius A., Cheeseman, Michael T., McNally, Eugene G., Carr, Andrew J., Thomas, Gethin P., Brown, Matthew A., Croucher, Peter I., Brown, Steve D. M., Cox, Roger D. and Thakker, Rajesh V. (2012) A Mouse with an N-Ethyl-N-Nitrosourea (ENU) Induced Trp589Arg Galnt3 Mutation Represents a Model for Hyperphosphataemic Familial Tumoural Calcinosis. PLoS One, 7 8 Article. No.e43205: .


Author Esapa, Christopher T.
Head, Rosie A.
Jeyabalan, Jeshmi
Evans, Holly
Hough, Tertius A.
Cheeseman, Michael T.
McNally, Eugene G.
Carr, Andrew J.
Thomas, Gethin P.
Brown, Matthew A.
Croucher, Peter I.
Brown, Steve D. M.
Cox, Roger D.
Thakker, Rajesh V.
Title A Mouse with an N-Ethyl-N-Nitrosourea (ENU) Induced Trp589Arg Galnt3 Mutation Represents a Model for Hyperphosphataemic Familial Tumoural Calcinosis
Journal name PLoS One  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2012-08
Sub-type Article
DOI 10.1371/journal.pone.0043205
Volume number 7
Issue number 8 Article. No.e43205
ISSN 1932-6203
Total pages 15
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2013
Language eng
Formatted abstract Mutations of UDP-N-acetyl-alpha-D-galactosamine polypeptide N-acetyl galactosaminyl transferase 3 (GALNT3) result in familial tumoural calcinosis (FTC) and the hyperostosis-hyperphosphataemia syndrome (HHS), which are autosomal recessive disorders characterised by soft-tissue calcification and hyperphosphataemia. To facilitate in vivo studies of these heritable disorders of phosphate homeostasis, we embarked on establishing a mouse model by assessing progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU), and identified a mutant mouse, TCAL, with autosomal recessive inheritance of ectopic calcification, which involved multiple tissues, and hyperphosphataemia; the phenotype was designated TCAL and the locus, Tcal. TCAL males were infertile with loss of Sertoli cells and spermatozoa, and increased testicular apoptosis. Genetic mapping localized Tcal to chromosome 2 (62.64-71.11 Mb) which contained the Galnt3. DNA sequence analysis identified a Galnt3 missense mutation (Trp589Arg) in TCAL mice. Transient transfection of wild-type and mutant Galnt3-enhanced green fluorescent protein (EGFP) constructs in COS-7 cells revealed endoplasmic reticulum retention of the Trp589Arg mutant and Western blot analysis of kidney homogenates demonstrated defective glycosylation of Galnt3 in Tcal/Tcal mice. Tcal/Tcal mice had normal plasma calcium and parathyroid hormone concentrations; decreased alkaline phosphatase activity and intact Fgf23 concentrations; and elevation of circulating 1,25-dihydroxyvitamin D. Quantitative reverse transcriptase-PCR (qRT-PCR) revealed that Tcal/Tcal mice had increased expression of Galnt3 and Fgf23 in bone, but that renal expression of Klotho, 25-hydroxyvitamin D-1α-hydroxylase (Cyp27b1), and the sodium-phosphate co-transporters type-IIa and -IIc was similar to that in wild-type mice. Thus, TCAL mice have the phenotypic features of FTC and HHS, and provide a model for these disorders of phosphate metabolism.
Keyword Homozygous Missense Mutation
O Linked Glycosylation
Alpha D Galactosamine
Skeletal Abnormalities
Targeted Inactivation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article
Collections: Official 2013 Collection
UQ Diamantina Institute Publications
 
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