Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity
Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity
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DOI：
10.1007/s00439-006-0197-y
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发表时间：
2006-09-01
期刊：
影响因子：
5.3
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
--
作者：
Eichers, Erica R.;Abd-El-Barr, Muhammad M.;Lupski, James R.
Bardet-Biedl综合征（BBS）是一种罕见的寡基因疾病，表现出临床和遗传异质性。虽然BBS表型在家族之间和家族内都是可变的，但该综合征的特征是发育和学习困难、轴后多指、肥胖、生殖功能减退、肾脏异常、视网膜营养不良和几个不太常见的特征。在BBS患者中已经鉴定出11个突变基因，并且预期存在更多的突变基因，因为大约20-30%的所有家族不能用已知的基因座来解释。为了研究BBS的发病机制，我们建立了一个小鼠空的小鼠同源物之一，Bbs 4，以评估一个基因的多效性小鼠Bbs表型的贡献。Bbs 4基因敲除小鼠尽管最初与同窝小鼠相比发育迟缓，但最终以性别依赖的方式变得肥胖，雌性比雄性更早且更严重。血液化学检查表明血脂异常，肝功能障碍的迹象，胰岛素和瘦素水平升高，使人联想到代谢综合征。与BBS患者一样，我们发现了年龄依赖性视网膜营养不良。行为评估显示，突变小鼠表现出更多的焦虑相关反应，并降低了社会优势。我们注意到，在裸小鼠中很少发生出生缺陷，包括神经管缺陷和子宫阴道积水。对这些无效小鼠的评估揭示了具有年龄依赖性的表达率和可变表达率的表型特征，部分重现了人类BBS表型。
Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.