Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1
Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1
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DOI：
10.1242/dmm.042614
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发表时间：
2020-03-01
影响因子：
4.3
通讯作者：
Pavan, William J.
中科院分区：
文献类型：
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作者：
Rodriguez-Gil, Jorge L.;Watkins-Chow, Dawn E.;Pavan, William J.
C1 型尼曼-匹克病 (NPC1) 是一种罕见的致命性神经退行性疾病，其特征是溶酶体中未酯化胆固醇和鞘糖脂的积累。这些亚细胞病理导致肝脾肿大、神经变性和过早死亡的表型。 NPC1 在临床表现的时间上具有极大的异质性，并且与多种致病性 NPC1 突变相关。为了研究 NPC1 的遗传结构，我们生成了一个新的 NPC1 小鼠模型，Npc1(em1Pav)。与对照相比，Npc1(em1Pav/em1Pav) 突变体表现出 NPC1 蛋白显着减少，并表现出 NPC1 的病理和生化特征。有趣的是，与 BALB/cJ 背景的 Npc1em1Pav/em1Pav 突变体相比，C57BL/6J 遗传背景的 Npc1em1Pav/em1Pav 突变体表现出更严重的内脏病理学和显着更短的寿命，这表明菌株特异性修饰剂有助于疾病的严重程度和生存。对混合 C57BL/6J 和 BALB/cJ 背景上的 202 个回交 N2 突变体的寿命进行 QTL 分析，检测到与 1 号和 7 号染色体上的标记存在显着连锁。这些修饰区域的发现表明，小鼠模型是分析人类罕见疾病的遗传学的有力工具，可用于增进对 NPC1 表型变异性的理解，并为患者诊断和治疗提供先进的选择。
Niemann-Pick disease type C1 (NPC1) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. NPC1 is extremely heterogeneous in the timing of clinical presentation and is associated with a wide spectrum of causative NPC1 mutations. To study the genetic architecture of NPC1, we have generated a new NPC1 mouse model, Npc1(em1Pav). Npc1(em1Pav/em1Pav) mutants showed notably reduced NPC1 protein compared to controls and displayed the pathological and biochemical hallmarks of NPC1. Interestingly, Npc1em1Pav/em1Pav mutants on a C57BL/6J genetic background showed more severe visceral pathology and a significantly shorter lifespan compared to Npc1em1Pav/em1Pav mutants on a BALB/cJ background, suggesting that strain-specific modifiers contribute to disease severity and survival. QTL analysis for lifespan of 202 backcross N2 mutants on a mixed C57BL/6J and BALB/cJ background detected significant linkage to markers on chromosomes 1 and 7. The discovery of these modifier regions demonstrates that mouse models are powerful tools for analyzing the genetics underlying rare human diseases, which can be used to improve understanding of the variability in NPC1 phenotypes and advance options for patient diagnosis and therapy.