Gorvin, Caroline M, Loh, Nellie Y, Stechman, Michael J, Falcone, Sara, Hannan, Fadil M ORCID: 0000-0002-2975-5170, Ahmad, Bushra N, Piret, Sian E, Reed, Anita AC, Jeyabalan, Jeshmi, Leo, Paul et al (show 17 more authors)
(2019)
Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis.
JOURNAL OF BONE AND MINERAL RESEARCH, 34 (7).
pp. 1324-1335.
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<sup>+/M149T</sup> ) mice, when compared with wild-type (Brd4<sup>+/+</sup> ) 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<sup>+/M149T</sup> and Brd4<sup>+/+</sup> mice, revealed differential expression of genes involved in vitamin D metabolism, cell differentiation, and apoptosis. Kidneys from Brd4<sup>+/M149T</sup> 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. © 2019 American Society for Bone and Mineral Research.
Item Type: | Article |
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Uncontrolled Keywords: | NEPHROLITHIASIS, NEPHROCALCINOSIS, MOUSE MODEL, BRD4 MUTATION |
Depositing User: | Symplectic Admin |
Date Deposited: | 03 Oct 2019 08:37 |
Last Modified: | 15 Mar 2024 05:30 |
DOI: | 10.1002/jbmr.3695 |
Open Access URL: | https://doi.org/10.1002/jbmr.3695 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3056830 |