Fhl1 W122S突变雌性老鼠出现晚发性心肌病(P5.265)

文摘

背景:x连锁scapuloperoneal肌病(X-SPM)是一种成人慢性疾病引起的FHL1 (LIM一半4。1)突变。尽管女性携带杂合的FHL1突变的影响,他们的表型是比半合温和男人。X-SPM有时与心肌病,FHL1基因突变导致孤立的心肌病,Emery-Dreifuss肌肉萎缩症,减少身体肌病,x连锁肌病姿势肌肉萎缩。FHL1被认为调解蛋白质-蛋白质之间的关系;然而,表型异质性的机制是未知的。我们以前生成的敲入小鼠模型有相同的突变(c。365G>C, p.W122S) as human patients with X-SPM, and found that mutant male mice developed late-onset slowly progressive myopathy, but not cardiac dysfunction. DESIGN/METHODS: We analyzed heterozygous and homozygous female mice. RESULTS:Exercise test showed transient mild muscle weakness (15[percnt] reduction) in both heterozygous and homozygous female mice at 10 months, but no gross pathological abnormalities in skeletal muscle at any age. Echocardiograms were normal at 10 months, but at 20 months, mutant female mice showed increased systolic diameter (wild: 2.74 ± 0.22 mm, mean ± SD; heterozygous: 3.13 ± 0.11 mm, P<0.01; homozygous: 3.08 ± 0.37 mm, P<0.05) and lower fractional shortening (wild: 31.1 ± 4.4[percnt], mean ± SD; heterozygous: 22.7 ± 2.5[percnt], P<0.01; homozygous: 22.4 ± 6.9[percnt], P<0.01). Histological analysis of heart revealed frequent extraordinarily large “box-shaped” nuclei in mutant female mice. Western blot demonstrated decreased Fhl1 protein levels in double mutant female mice in heart, but not in skeletal muscle. Proteomic analysis of heart from 20 month-old double mutant female mice suggests that integrin signaling pathway is involved in cardiac dysfunction in this mouse model. CONCLUSIONS:Fhl1 W122S female mice manifest late-onset cardiac dysfunction. This is the first mouse model of FHL1-related cardiomyopathy.

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