Awano Hiroyuki, Blaeser Anthony, Keramaris Elizabeth, Xu Lei, Tucker Jason, Wu Bo, Lu Pei, Lu Qi L
McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina.
McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, North Carolina.
Am J Pathol. 2015 Jul;185(7):2025-37. doi: 10.1016/j.ajpath.2015.03.017. Epub 2015 May 12.
Mutations in fukutin-related protein (FKRP) gene are characterized with lack of functionally glycosylated α-dystroglycan (F-α-DG). Surprisingly, a few muscle fibers express strong F-α-DG. Herein, we investigated the restoration of F-α-DG in the FKRP mutant muscles and showed that the restoration of glycosylation is associated with muscle regeneration and dependent on the expression of both like-glycosyltransferase (LARGE) and partially functional FKRP. F-α-DG in the regenerating fibers reaches up to normal levels and lasts for >4 weeks, but no up-regulation of the LARGE and FKRP is detected during the regeneration process. The FKRP protein with P448L mutation is sufficient for functional glycosylation of α-DG in regenerating fibers, but not in mature fibers. Thus, factors other than FKRP enable regenerating fibers to produce functional α-DG, compensating for the defect in FKRP function. Identification of factors other than LARGE and FKRP could generate new approaches for restoration of F-α-DG in mature muscle fibers with defects in FKRP functions.
福斯素相关蛋白（FKRP）基因突变的特征是缺乏功能糖基化的α-肌营养不良蛋白（F-α-DG）。令人惊讶的是，少数肌纤维表达强F-α-DG。在此，我们研究了FKRP突变肌肉中F-α-DG的恢复情况，并表明糖基化的恢复与肌肉再生相关，且依赖于类糖基转移酶（LARGE）和部分功能性FKRP的表达。再生纤维中的F-α-DG达到正常水平并持续超过4周，但在再生过程中未检测到LARGE和FKRP的上调。具有P448L突变的FKRP蛋白足以使再生纤维中的α-DG进行功能性糖基化，但不能使成熟纤维中的α-DG进行功能性糖基化。因此，除FKRP外的其他因素使再生纤维能够产生功能性α-DG，弥补FKRP功能缺陷。鉴定除LARGE和FKRP外的其他因素可为恢复FKRP功能缺陷的成熟肌纤维中的F-α-DG产生新方法。
