We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

我们确定了六个近亲先天性挛缩，脊柱侧弯和矮小的近亲家庭中的十个人。外显子组测序显示，每个受影响的人都是两种不同的罕见变体（c.470G> T [p.Cys157Phe]或c.469T> C [p.Cys157Arg]）纯合，影响肌球蛋白轻链的相同残基，可磷酸化，快速骨骼肌（MYLPF）。在第七个家庭，在c.487G> A（p.Gly163Ser）变种MYLPF出现从头的父亲是谁传递给他的儿子。在由七个具有显性遗传的DA的个体组成的第八个家庭中，在所有四个测试的个体中均存在c.98C> T（p.Ala33Val）变异。MYLPF的变体是显性和隐性遗传的DA的基础。Mylpf蛋白模型表明，与显性DA相关的残基与肌球蛋白相互作用，而在隐性DA家族中改变的残基仅间接损害这种相互作用。对患儿截肢的脚进行病理和组织学检查，发现骨骼肌完全不存在（即节段性肌再生不良）。为了研究这一发现的机制，我们通过敲除斑马鱼mylpfa生成了部分MYLPF损伤的动物模型。该mylpfa突变减少了主干收缩力和完整的胸鳍瘫痪，这表明mylpf受损最严重影响肢体运动。Mylpfa突变型肌无力在阑尾肌中最明显，其原因是肌球蛋白活性降低和纤维变性。总体而言，我们的研究结果表明，MYLPF功能的部分丧失可导致先天性挛缩，这可能是由于远端肢体骨骼肌变性所致。