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Mice with a Brd4 mutation represent a new model of nephrocalcinosis

Authors

  • C.M. Gorvin
  • N.Y. Loh
  • M.J. Stechman
  • S. Falcone
  • F.M. Hannan
  • B.N. Ahmad
  • S.E. Piret
  • A.A.C. Reed
  • J. Jeyabalan
  • P. Leo
  • M. Marshall
  • S. Sethi
  • P. Bass
  • I. Roberts
  • J. Sanderson
  • S. Wells
  • T.A. Hough
  • L. Bentley
  • P.T. Christie
  • M.M. Simon
  • A.M. Mallon
  • H. Schulz
  • R.D. Cox
  • M.A. Brown
  • N. Huebner
  • S.D. Brown
  • R.V. Thakker

Journal

  • Journal of Bone and Mineral Research

Citation

  • J Bone Miner Res 34 (7): 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(+/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.


DOI

doi:10.1002/jbmr.3695