Cotman Susan L, Vrbanac Vladimir, Lebel Lori-Anne, Lee Richard L, Johnson Kevin A, Donahue Leah-Rae, Teed Allison M, Antonellis Kristen, Bronson Roderick T, Lerner Terry J, MacDonald Marcy E
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.
Hum Mol Genet. 2002 Oct 15;11(22):2709-21. doi: 10.1093/hmg/11.22.2709.
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 approximately 1 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.
青少年型神经元蜡样脂褐质沉积症（JNCL；巴顿病）的特征是标志性的膜沉积物和中枢神经系统（CNS）神经元的丧失。该疾病的大多数病例是由于CLN3基因中约1 kb缺失的隐性遗传，该基因编码巴顿蛋白。为了研究常见的JNCL突变，我们将相同的基因组DNA缺失引入小鼠CLN3同源物（Cln3）中，以创建Cln3(Deltaex7/8)基因敲入小鼠。Cln3(Deltaex7/8)等位基因产生可变剪接的mRNA，包括预测非截短蛋白的变体，以及在外周和中枢神经系统细胞胞质中检测到的突变巴顿蛋白。此外，Cln3(Deltaex7/8)纯合子从出生前就表现出类似JNCL的膜沉积物的积累，与巴顿蛋白水平成比例，巴顿蛋白在肝脏和特定神经元群体中含量很高。然而，肝酶和中枢神经系统发育正常。相反，Cln3(Deltaex7/8)小鼠表现出视网膜、大脑皮层和小脑的隐性遗传退行性变化，以及神经功能缺损和过早死亡。因此，常见JNCL突变对中枢神经系统的有害影响与膜沉积本身并没有很好的相关性，相反，这表明一种特定的巴顿蛋白活性对中枢神经系统神经元的存活至关重要。
