Eichers Erica R, Abd-El-Barr Muhammad M, Paylor Richard, Lewis Richard Alan, Bi Weimin, Lin Xiaodi, Meehan Thomas P, Stockton David W, Wu Samuel M, Lindsay Elizabeth, Justice Monica J, Beales Philip L, Katsanis Nicholas, Lupski James R
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza Room 604B, Houston, TX 77030, USA.
Hum Genet. 2006 Sep;120(2):211-26. doi: 10.1007/s00439-006-0197-y. Epub 2006 Jun 23.
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.
巴德-比埃尔综合征（BBS）是一种罕见的寡基因疾病，具有临床和遗传异质性。尽管BBS的表型在不同家族之间以及家族内部都存在差异，但该综合征的特征是发育和学习困难、轴后多指（趾）畸形、肥胖、生殖器发育不全、肾脏异常、视网膜营养不良以及一些较少见的特征。已鉴定出11个在BBS患者中发生突变的基因，预计还存在更多基因，因为约20%-30%的家族无法用已知基因座来解释。为了研究BBS的病因发病机制，我们构建了一种小鼠模型，使其一个小鼠同源基因Bbs4缺失，以评估一个基因对多效性小鼠Bbs表型的影响。Bbs4基因敲除小鼠虽然最初比同窝小鼠体型小，但最终会以性别依赖的方式变得肥胖，雌性比雄性更早且更严重。血液化学检测表明血脂异常、肝功能障碍迹象以及胰岛素和瘦素水平升高，这让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与焦虑相关的反应，且社会优势降低。我们注意到基因敲除小鼠中罕见的出生缺陷，包括神经管缺陷和阴道积血。对这些基因敲除小鼠的评估揭示了具有年龄依赖性外显率和可变表达性的表型特征，部分重现了人类BBS表型。
