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首页> 外文期刊>PLoS One >A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy
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A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy

机译：远端肌营养不良症家族中的新型FLNC移码和OBSCN变异

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A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously reported FLNC mutation (c.5160delC) that was identified in patients and in asymptomatic carriers of three Bulgarian families with distal muscular dystrophy, indicating a low penetrance of the FLNC frameshift mutations. Given these similarities, we believe that the two FLNC mutations alone can be causative of distal myopathy without full penetrance. Moreover, comparative analysis of the clinical manifestations indicates that patients of the French family show an earlier onset and a complete segregation of the disease. As a possible explanation of this, the two French patients also carry a OBSCN c.13330CT (p.Arg4444Trp) mutation. The p.Arg4444Trp variant is localized within the OBSCN Ig59 domain that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicate that this OBSCN p.Arg4444Trp mutation decreases titin binding by ~15-fold. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutation, can cooperatively affect myofibril stability and increase the penetrance of muscular dystrophy in the French family.
机译：在受远端肌病影响的一个法国家庭的两个成员和一个健康的亲戚中鉴定出一个新的FLNC c.5161delG（p.Gly1722ValfsTer61）突变。该FLNC c.5161delG突变与先前报道的FLNC突变（c.5160delC）相距一个核苷酸，该突变已在三个远端保加利亚营养不良的保加利亚家庭的患者和无症状携带者中发现，表明FLNC移码突变的低渗透性。鉴于这些相似性，我们认为仅这两个FLNC突变就可能导致远端肌病而没有完全外显。此外，对临床表现的比较分析表明，该法国家庭的患者显示出该疾病的较早发作和完全隔离。对此的可能解释是，两名法国患者还携带OBSCN c.13330C> T（p.Arg4444Trp）突变。 p.Arg4444Trp变体位于OBSCN Ig59域内，该域与Ig58一起在Z盘上与titin的ZIg9 / ZIg10域结合。结构和功能研究表明，这种OBSCN p.Arg4444Trp突变可使肌动蛋白结合降低约15倍。关于这一点，我们建议OBSCN p.Arg4444Trp变体和FLNC c.5161delG突变的组合可以协同影响肌原纤维的稳定性，并增加法国家族中肌营养不良症的渗透性。

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