Herbert Pratt C, Potter Christopher S, Fairfield Heather, Reinholdt Laura G, Bergstrom David E, Harris Belinda S, Greenstein Ian, Dadras Soheil S, Liang Bruce T, Schofield Paul N, Sundberg John P
The Jackson Laboratory, Bar Harbor, ME, USA.
The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Exp Mol Pathol. 2015 Apr;98(2):164-72. doi: 10.1016/j.yexmp.2015.01.015. Epub 2015 Feb 7.
Studies of spontaneous mutations in mice have provided valuable disease models and important insights into the mechanisms of human disease. Ruffled (rul) is a new autosomal recessive mutation causing abnormal hair coat in mice. The rul allele arose spontaneously in the RB156Bnr/EiJ inbred mouse strain. In addition to an abnormal coat texture, we found diffuse epidermal blistering, abnormal electrocardiograms (ECGs), and ventricular fibrosis in mutant animals. Using high-throughput sequencing (HTS) we found a frameshift mutation at 38,288,978bp of chromosome 13 in the desmoplakin gene (Dsp). The predicted mutant protein is truncated at the c-terminus and missing the majority of the plakin repeat domain. The phenotypes found in Dsp(rul) mice closely model a rare human disorder, Carvajal-Huerta syndrome. Carvajal-Huerta syndrome (CHS) is a rare cardiocutaneous disorder that presents in humans with wooly hair, palmoplantar keratoderma and ventricular cardiomyopathy. CHS results from an autosomal recessive mutation on the 3' end of desmoplakin (DSP) truncating the full length protein. The Dsp(rul) mouse provides a new model to investigate the pathogenesis of CHS, as well as the underlying basic biology of the adhesion molecules coded by the desmosomal genes.
对小鼠自发突变的研究提供了有价值的疾病模型，并为深入了解人类疾病机制提供了重要见解。Ruffled（rul）是一种新的常染色体隐性突变，可导致小鼠毛发异常。rul等位基因在RB156Bnr/EiJ近交小鼠品系中自发产生。除了毛发质地异常外，我们还在突变动物中发现了弥漫性表皮水疱、异常心电图（ECG）和心室纤维化。通过高通量测序（HTS），我们在桥粒斑蛋白基因（Dsp）的13号染色体38,288,978bp处发现了一个移码突变。预测的突变蛋白在c端被截断，缺失了大部分的plakin重复结构域。在Dsp（rul）小鼠中发现的表型与一种罕见的人类疾病——卡瓦哈尔-韦尔塔综合征非常相似。卡瓦哈尔-韦尔塔综合征（CHS）是一种罕见的心皮肤疾病，在人类中表现为羊毛状毛发、掌跖角化病和心室心肌病。CHS是由桥粒斑蛋白（DSP）3'端的常染色体隐性突变导致全长蛋白截断引起的。Dsp（rul）小鼠为研究CHS的发病机制以及桥粒基因编码的粘附分子的潜在基础生物学提供了一个新模型。
