Targeted disruption of the mouse sphingolipid activator protein gene: A complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids
Targeted disruption of the mouse sphingolipid activator protein gene: A complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids
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DOI：
10.1093/hmg/5.6.711
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发表时间：
1996-06-01
影响因子：
3.5
通讯作者：
Suzuki, K
中科院分区：
文献类型：
--
作者：
Fujita, N;Suzuki, K;Suzuki, K
四种已确定或推定的鞘脂激活蛋白源自由单个基因编码的大前体蛋白。除了产生四种鞘脂激活蛋白之外，前体蛋白被怀疑具有其自身的功能，例如脂质结合/转运蛋白或神经营养因子。该基因似乎还编码支持细胞主要硫酸化糖蛋白。人们已经注意到许多其他具有不同功能的蛋白质具有序列相似性。由于起始密码子突变，该基因完全缺陷的一个家庭中的一名患者和一名胎儿表现出复杂的病理和生化异常。鞘脂激活蛋白前体失活基因的纯合突变小鼠表现出两种不同的临床表型——新生儿致命和晚发型。后者在 20 天左右出现快速进展的神经症状，并在 35-38 天死亡。 30天时，主要病理是整个神经系统以及肝脏和脾脏的异常细胞中出现严重的髓鞘形成不足和高碘酸希夫阳性物质。最显着的是，脑、肝、肾中的乳糖神经酰胺以及神经酰胺、葡萄糖神经酰胺、半乳糖神经酰胺、脑硫苷脂和三糖神经酰胺异常增加，并且它们的分解代谢在培养的成纤维细胞中异常缓慢。脑神经节苷脂普遍增加，特别是单唾液酸神经节苷脂。其临床、病理和生化表型与人类疾病非常相似。该模型不仅可以进一步阐明四种鞘脂激活蛋白的生理功能，而且还有助于探索前体蛋白的假定功能。
The four established or putative sphingolipid activator proteins derive from a large precursor protein encoded by a single gene. In addition to generating the four sphingolipid activator proteins, the precursor protein is suspected of having functions of its own, as, for example, a lipid binding/transport protein or a neurotrophic factor. The gene also appears to encode the Sertoli cell major sulfated glycoprotein. Sequence similarities have been noted with many other proteins of diverse functions. One patient and a fetus in a single family with a complete defect of this gene due to a mutation in the initiation codon exhibited complex pathological and biochemical abnormalities. Mutant mice homozygous for an inactivated gene of the sphingolipid activator protein precursor exhibit two distinct clinical phenotypes-neonatally fatal and later-onset. The latter develop rapidly progressive neurological signs around 20 days and die by 35-38 days. At 30 days, severe hypomyelination and periodic acid-Schiff-positive materials throughout the nervous system and in abnormal cells in the liver and spleen are the main pathology. Most prominently lactosylceramide, and additionally ceramide, glucosylceramide, galactosylceramide, sulfatide, and globotriaosylceramide are abnormally increased in the brain, liver, kidney, and their catabolism abnormally slow in cultured fibroblasts. Brain gangliosides are generally increased, particularly the monosialogangliosides. The clinical, pathological and biochemical phenotype closely resembles that of the human disease. This model not only allows further clarification of the physiological functions of the four individual sphingolipid activator proteins but also should be useful to explore putative functions of the precursor protein.