Mice with a Brd4 mutation represent a new model of nephrocalcinosis

Caroline M Gorvin, Nellie Loh, Michael Stechman, Sara Falcone, Fadil M Hannan, Bushra Ahmad, Sian Piret, Anita Reed, Jeshmi Jeyabalan, Paul Leo, Mhairi Marshall, Siddharth Sethi, Paul Bass, Ian Roberts, Jeremy Sanderson, Sara Wells, Tertius Hough, Liz Bentley, Paul Christie, Michelle SimonAnn-Marie Mallon, Herbert Schulz, Roger Cox, Matthew Brown, Norbert Huebner, Steve Brown, Rajesh V Thakker

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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.
Original languageEnglish
Pages (from-to)1324-1335
Number of pages12
JournalJournal of Bone and Mineral Research
Issue number7
Early online date4 Mar 2019
Publication statusPublished - Jul 2019

Bibliographical note

© 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.




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