Universität zu Köln

Gorvin, Caroline M., Loh, Nellie Y., Stechman, Michael J., Falcone, Sara, Hannan, Fadil M., Ahmad, Bushra N., Piret, Sian E., Reed, Anita A. C., 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, Ann-Marie, Schulz, Herbert, Cox, Roger D., Brown, Matthew A., Huebner, Norbert, Brown, Steve D. and Thakker, Rajesh V. (2019). Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis. J. Bone Miner. Res., 34 (7). S. 1324 - 1336. HOBOKEN: WILEY. ISSN 1523-4681

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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 similar to 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 similar to 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. (c) 2019 American Society for Bone and Mineral Research.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gorvin, Caroline M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Loh, Nellie Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stechman, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Falcone, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Hannan, Fadil M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahmad, Bushra N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Piret, Sian E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reed, Anita A. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jeyabalan, Jeshmi UNSPECIFIED UNSPECIFIED UNSPECIFIED Leo, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshall, Mhairi UNSPECIFIED UNSPECIFIED UNSPECIFIED Sethi, Siddharth UNSPECIFIED UNSPECIFIED UNSPECIFIED Bass, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Roberts, Ian UNSPECIFIED UNSPECIFIED UNSPECIFIED Sanderson, Jeremy UNSPECIFIED UNSPECIFIED UNSPECIFIED Wells, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Hough, Tertius A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bentley, Liz UNSPECIFIED UNSPECIFIED UNSPECIFIED Christie, Paul T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Michelle M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mallon, Ann-Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz, Herbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Cox, Roger D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brown, Matthew A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Huebner, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Brown, Steve D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thakker, Rajesh V. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-136074
DOI:	10.1002/jbmr.3695
Journal or Publication Title:	J. Bone Miner. Res.
Volume:	34
Number:	7
Page Range:	S. 1324 - 1336
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1523-4681
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RENAL EPITHELIAL-CELLS; MOLECULAR-MECHANISMS; STONE FORMATION; GENOME-WIDE; MOUSE MODEL; CALCIUM; NEPHROLITHIASIS; EXPRESSION; RECEPTOR; PROTEIN Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13607