Cln3Δex7/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth
Cln3Δex7/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth
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DOI：
10.1093/hmg/11.22.2709
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发表时间：
2002-10-15
影响因子：
3.5
通讯作者：
MacDonald, ME
中科院分区：
文献类型：
--
作者：
Cotman, SL;Vrbanac, V;MacDonald, ME
幼年型神经元蜡样质脂褐质沉积症（JNCL; Batten.这种疾病的特征是标志性的膜沉积和中枢神经系统（CNS）神经元的丢失：大多数病例是由于编码battenin的CLN 3基因中类似于1 kb缺失的隐性遗传。为了研究常见的JNCL突变，我们将相同的基因组DNA缺失引入到鼠CLN 3同源物（Cln 3）中以产生Cln 3（Deltaex 7/8）敲入小鼠。Cln 3（Deltaex 7/8）等位基因产生选择性剪接的mRNA，包括预测非截短蛋白的变体，以及在外周和CNS细胞的细胞质中检测到的突变battenin。此外，Cln 3（Deltaex 7/8）纯合子表现出JNCL样膜沉积物从出生前的积累，成比例的battenin水平，这是高的肝脏和选择的神经元群体。然而，肝酶和CNS发育正常。相反，Cln 3（Deltaex 7/8）小鼠显示视网膜、大脑皮层和小脑的recrecently遗传的退行性变化，以及神经缺陷和过早死亡。因此，常见的JNCL突变对CNS的有害影响与膜沉积本身没有很好的相关性，而是表明了一种对CNS神经元存活至关重要的特异性battenin活性。
Juvenile-onset neuronal ceroid lipofuscinosis (JNCL; Batten. disease) features hallmark membrane deposits and loss of central nervous system (CNS) neurons: Most cases of the disease are due to recessive inheritance of an similar to1 kb deletion in the CLN3 gene, encoding battenin. To investigate the common JNCL mutation, we have introduced an identical genomic DNA deletion into the murine CLN3 homologue (Cln3) to create Cln3(Deltaex7/8) knock-in mice. The Cln3(Deltaex7/8) allele produced alternatively spliced mRNAs, including a variant predicting non-truncated protein, as well as mutant battenin that was detected in the cytoplasm of cells in the periphery and CNS. Moreover, Cln3(Deltaex7/8) homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations. However, liver enzymes and CNS development were normal. Instead, Cln3(Deltaex7/8) mice displayed recessively inherited degenerative changes in retina, cerebral cortex and cerebellum, as well as neurological deficits and premature death. Thus, the harmful impact of the common JNCL mutation on the CNS was not well correlated with membrane deposition per se, suggesting instead a specific battenin activity that is essential for the survival of CNS neurons.