Abstract：
Spinal Muscular Atrophy with Respiratory Distress (SMARD1) is a lethal infantile disease, characterized by the loss of motor neurons leading to muscular atrophy, diaphragmatic paralysis, and weakness in the trunk and limbs. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause a wide spectrum of motor neuron disease. Though mutations in IGHMBP2 are mostly associated with SMARD1, milder alleles cause the axonal neuropathy, Charcot-Marie-Tooth disease type 2S (CMT2S), and some null alleles are potentially a risk factor for sudden infant death syndrome (SIDS). Variant heterogeneity studied using an allelic series can be informative in order to create a broad spectrum of models that better exhibit the human variation. We previously identified the nmd2J mouse model of SMARD1, as well as two milder CMT2S mouse models. Here, we used CRISPR-Cas9 genome editing to create three new, more severe Ighmbp2 mouse models of SMARD1, including a null allele, a deletion of C495 (C495del) and a deletion of L362 (L362del). Phenotypic characterization of the IGHMBP2L362del homozygous mutants and IGHMBP2C495del homozygous mutants respectively show a more severe disease presentation than the previous nmd2J model. The IGHMBP2L362del mutants lack a clear denervation in the diaphragm while the IGHMBP2C495del mutants display a neurogenic diaphragmatic phenotype as observed in SMARD1 patients. Characterization of the Ighmbp2-null model indicated neo-natal lethality (median lifespan = 0.5 days). These novel strains expand the spectrum of SMARD1 models to better reflect the clinical continuum observed in the human patients with various IGHMBP2 recessive mutations.
摘要：
脊髓性肌萎缩伴呼吸窘迫（SMARD1）是一种致命的婴儿疾病，以运动神经元丢失导致肌肉萎缩为特征，膈肌麻痹,躯干和四肢无力。IGHMBP2是一种广泛表达的DNA/RNA解旋酶，已被证明会引起广泛的运动神经元疾病。虽然IGHMBP2的突变主要与SMARD1相关，但较温和的等位基因会导致轴索神经病变，Charcot-Marie-Tooth病2S型（CMT2S），一些无效等位基因是婴儿猝死综合征（SIDS）的潜在危险因素。使用等位基因系列研究的变体异质性可以提供信息，以创建更好地展示人类变异的广谱模型。我们先前鉴定了SMARD1的nmd2J小鼠模型,以及两种较温和的CMT2S小鼠模型。这里,我们使用CRISPR-Cas9基因组编辑创建了三个新的，SMARD1的更严重的Ighmbp2小鼠模型，包括一个无效等位基因，C495的缺失(C495del)和L362的缺失(L362del)。IGHMBP2L362del纯合突变体和IGHMBP2C495del纯合突变体的表型表征分别显示比先前的nmd2J模型更严重的疾病呈现。IGHMBP2L362del突变体在隔膜中缺乏明显的去神经支配，而IGHMBP2C495del突变体显示出在SMARD1患者中观察到的神经源性隔膜表型。Ighmbp2无效模型的表征表明新生儿死亡率(中位寿命=0.5天)。这些新型菌株扩展了SMARD1模型的谱，以更好地反映在具有各种IGHMBP2隐性突变的人类患者中观察到的临床连续性。
