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Mice with a Brd4 mutation represent a new model of nephrocalcinosis

Item Type:Article
Title:Mice with a Brd4 mutation represent a new model of nephrocalcinosis
Creators Name:Gorvin, C.M. and Loh, N.Y. and Stechman, M.J. and Falcone, S. and Hannan, F.M. and Ahmad, B.N. and Piret, S.E. and Reed, A.A.C. and Jeyabalan, J. and Leo, P. and Marshall, M. and Sethi, S. and Bass, P. and Roberts, I. and Sanderson, J. and Wells, S. and Hough, T.A. and Bentley, L. and Christie, P.T. and Simon, M.M. and Mallon, A.M. and Schulz, H. and Cox, R.D. and Brown, M.A. and Huebner, N. and Brown, S.D. and Thakker, R.V.
Abstract:Nephrolithiasis (NL) and nephrocalcinosis (NC), which comprise renal calcification of the collecting system and parenchyma, respectively, have a multifactorial etiology with environmental and genetic determinants and affect ∼10% of adults by age 70 years. Studies of families with hereditary NL and NC have identified >30 causative genes that have increased our understanding of extracellular calcium homeostasis and renal tubular transport of calcium. However, these account for <20% of the likely genes that are involved, and to identify novel genes for renal calcification disorders, we investigated 1745 12-month-old progeny from a male mouse that had been treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for radiological renal opacities. This identified a male mouse with renal calcification that was inherited as an autosomal dominant trait with >80% penetrance in 152 progeny. The calcification consisted of calcium phosphate deposits in the renal papillae and was associated with the presence of the urinary macromolecules osteopontin and Tamm-Horsfall protein, which are features found in Randall's plaques of patients with NC. Genome-wide mapping located the disease locus to a ∼30 Mbp region on chromosome 17A3.3-B3 and whole-exome sequence analysis identified a heterozygous mutation, resulting in a missense substitution (Met149Thr, M149T), in the bromodomain-containing protein 4 (BRD4). The mutant heterozygous (Brd4(+/M149T)) mice, when compared with wild-type (Brd4(+/+)) mice, were normocalcemic and normophosphatemic, with normal urinary excretions of calcium and phosphate, and had normal bone turnover markers. BRD4 plays a critical role in histone modification and gene transcription, and cDNA expression profiling, using kidneys from Brd4(+/M149T) and Brd4(+/+) mice, revealed differential expression of genes involved in vitamin D metabolism, cell differentiation, and apoptosis. Kidneys from Brd4(+/M149T) mice also had increased apoptosis at sites of calcification within the renal papillae. Thus, our studies have established a mouse model, due to a Brd4 Met149Thr mutation, for inherited NC.
Keywords:Nephrolithiasis, Nephrocalcinosis, Mouse Model, Brd4 Mutation, Animals, Mice
Source:Journal of Bone and Mineral Research
ISSN:0884-0431
Publisher:Wiley
Volume:34
Number:7
Page Range:1324-1335
Date:July 2019
Official Publication:https://doi.org/10.1002/jbmr.3695
PubMed:View item in PubMed

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