Mice with a Brd4 mutation represent a new model of nephrocalcinosis

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Item Type:	Article
Title:	Mice with a Brd4 mutation represent a new model of nephrocalcinosis
Creators Name:	Gorvin, C.M., Loh, N.Y., Stechman, M.J., Falcone, S., Hannan, F.M., Ahmad, B.N., Piret, S.E., Reed, A.A.C., Jeyabalan, J., Leo, P., Marshall, M., Sethi, S., Bass, P., Roberts, I., Sanderson, J., Wells, S., Hough, T.A., Bentley, L., Christie, P.T., Simon, M.M., Mallon, A.M., Schulz, H., Cox, R.D., Brown, M.A., Huebner, N., 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
Additional Information:	Copyright © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Official Publication:	https://doi.org/10.1002/jbmr.3695
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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