Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies
Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies
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DOI：
10.1093/brain/awn335
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发表时间：
2009-02-01
期刊：
影响因子：
14.5
通讯作者：
Brown, S. C.
中科院分区：
文献类型：
--
作者：
Ackroyd, M. R.;Skordis, L.;Brown, S. C.
FKRP相关蛋白（FKRP）的突变导致一组常见的肌营养不良症，从成人发病的肢带型肌营养不良症到伴有相关结构性脑受累的严重先天性形式，包括肌眼脑疾病。这些疾病的一个共同特征是骨骼肌肌营养不良蛋白聚糖糖基化的可变减少。为了深入了解发病机制和临床变异性，我们产生了两个品系的小鼠，第一个含有错义突变和新霉素盒，FKRP-Neo（Tyr 307 Asn），第二个仅含有FKRPTyr 307 Asn突变。我们以前在几个家庭中将这种错义突变与严重的肌眼脑表型相关联。纯合子Fkrp-Neo（Tyr 307 Asn）小鼠出生后不久死亡，并显示肌肉、眼睛和大脑中肌营养不良蛋白聚糖的层粘连蛋白结合表位减少，FKRP转录水平降低。纯合子Fkrp（Tyr 307 Asn）小鼠在6个月龄内未表现出可辨别的表型，这与在具有相同突变的患者中观察到的严重临床病程相反。这些结果表明，FKRP相关肌营养不良症的小鼠模型的产生需要敲低而不是敲入策略，以产生疾病表型。
Mutations in fukutin related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement, including Muscle Eye Brain disease. A common feature of these disorders is the variable reduction in the glycosylation of skeletal muscle -dystroglycan. In order to gain insight into the pathogenesis and clinical variability, we have generated two lines of mice, the first containing a missense mutation and a neomycin cassette, FKRP-Neo(Tyr307Asn) and the second containing the FKRPTyr307Asn mutation alone. We have previously associated this missense mutation with a severe muscleeyebrain phenotype in several families. Homozygote Fkrp-Neo(Tyr307Asn) mice die soon after birth and show a reduction in the laminin-binding epitope of -dystroglycan in muscle, eye and brain, and have reduced levels of FKRP transcript. Homozygous Fkrp(Tyr307Asn) mice showed no discernible phenotype up to 6 months of age, contrary to the severe clinical course observed in patients with the same mutation. These results suggest the generation of a mouse model for FKRP related muscular dystrophy requires a knock-down rather than a knock-in strategy in order to give rise to a disease phenotype.