Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), leading to muscle weakness and loss of sensation in the hands and feet. A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.

中文翻译：

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使用小鼠模型测试 SIPA1L2 作为 CMT1A 的修饰剂

夏科-玛丽-图思病 1A 型 (CMT1A) 是一种由外周髓磷脂蛋白 22 (PMP22) 重复引起的脱髓鞘性周围神经病，导致肌肉无力和手脚感觉丧失。遗传性神经病联盟最近对 CMT1A 患者进行的一项仅病例全基因组关联研究发现，足背屈强度与信号诱导增殖相关 1 像 2 (SIPA1L2) 变异之间存在很强的关联，表明它可能是一种遗传修饰剂的疾病。为了验证 SIPA1L2 作为候选修饰剂并评估其作为治疗靶点的潜力，我们对 Sipa1l2 基因的外显子 1（包括起始密码子）进行了改造，并将其与 CMT1A 的 C3-PMP22 小鼠模型杂交。神经肌肉表型分析表明，C3-PMP22 小鼠中 Sipa1l2 缺失保留了通过倒置钢丝悬挂持续时间测定的肌肉耐力，并改变了股神经轴突形态测量，例如髓磷脂厚度。基因表达变化表明 Sipa1l2 参与胆固醇生物合成，这一途径也与 C3-PMP22 小鼠有关。尽管 Sipa1l2 缺失确实影响了 CMT1A 相关表型，从而验证了遗传相互作用，但对神经病变的总体影响很轻微。