Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis
Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis
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DOI：
10.1002/jbmr.3695
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发表时间：
2019-07-01
影响因子：
6.2
通讯作者：
Thakker，Rajesh V.
中科院分区：
文献类型：
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作者：
Gorvin，Caroline M.;Loh，Nellie Y.;Thakker，Rajesh V.
肾结石（NL）和肾钙质沉着症（NC）分别包括集合系统和实质的肾钙化，具有环境和遗传决定因素的多因素病因学，影响70岁以上约10%的成年人。对遗传性NL和NC家族的研究已经确定了>30个致病基因，这些基因增加了我们对细胞外钙稳态和肾小管钙转运的理解。然而，这些占可能涉及的基因的<20%，为了鉴定肾脏钙化疾病的新基因，我们研究了1745只12个月大的雄性小鼠后代，这些小鼠接受了化学诱变剂N-乙基-N-亚硝基脲（ENU）治疗放射性肾混浊。这确定了一只患有肾钙化的雄性小鼠，其作为常染色体显性性状遗传，在152个后代中具有>80%的遗传率。钙化由肾乳头中的磷酸钙沉积物组成，并与尿大分子骨桥蛋白和Tamm-Horsfall蛋白的存在相关，这是NC患者Randall斑块中发现的特征。全基因组图谱将疾病基因座定位到染色体17 A3.3-B3上的130 Mbp区域，全外显子组序列分析发现了一个杂合突变，导致含溴结构域蛋白4（BRD 4）中的错义取代（Met 149 Thr、M149 T）。突变杂合子与野生型（Brd 4 +/+）小鼠相比，（Brd 4 +/M149 T）小鼠血钙和血磷正常，尿钙和磷酸盐排泄正常，骨转换标志物正常。使用Brd 4 +/M149 T和Brd 4 +/+小鼠的肾脏，揭示了参与维生素D代谢、细胞分化和凋亡的基因的差异表达。Brd 4 +/M149 T小鼠的肾脏在肾乳头内的钙化部位也具有增加的细胞凋亡。因此，我们的研究建立了一个小鼠模型，由于aBrd 4 Met 149 Thr突变，遗传性NC。© 2019美国骨与矿物质研究学会。
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 mutagenN‐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.BRD4plays a critical role in histone modification and gene transcription, and cDNA expression profiling, using kidneys fromBrd4+/M149TandBrd4+/+mice, revealed differential expression of genes involved in vitamin D metabolism, cell differentiation, and apoptosis. Kidneys fromBrd4+/M149Tmice also had increased apoptosis at sites of calcification within the renal papillae. Thus, our studies have established a mouse model, due to aBrd4Met149Thr mutation, for inherited NC. © 2019 American Society for Bone and Mineral Research.