Premium
Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis
Author(s) -
Gorvin Caroline M,
Loh Nellie Y,
Stechman Michael J,
Falcone Sara,
Hannan Fadil M,
Ahmad Bushra N,
Piret Sian E,
Reed Anita AC,
Jeyabalan Jeshmi,
Leo Paul,
Marshall Mhairi,
Sethi Siddharth,
Bass Paul,
Roberts Ian,
Sanderson Jeremy,
Wells Sara,
Hough Tertius A,
Bentley Liz,
Christie Paul T,
Simon Michelle M,
Mallon AnnMarie,
Schulz Herbert,
Cox Roger D,
Brown Matthew A,
Huebner Norbert,
Brown Steve D,
Thakker Rajesh V
Publication year - 2019
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3695
Subject(s) - nephrocalcinosis , hypercalciuria , endocrinology , biology , medicine , calcification , genetics , kidney , urinary system
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. © 2019 American Society for Bone and Mineral Research.