Pathophysiology & therapeutics: Fukutin related protein(FKRP) muscular dystrophy

肢体带状肌营养不良21 （LGMD2I）患者具有福古汀相关蛋白（FKRP）突变，并表现出异常广泛的临床表型。由于这种临床变异性的基础尚未完全了解，我们提出了一个涉及患者和互补小鼠模型研究的合作项目，以评估LGMD2I的发病机制和治疗策略。我们将定义LGMD2I患者的临床、分子和生化特征，以更好地了解这种疾病临床表现的可变性。FKRP突变患者将接受年度临床评估，包括标准化骨骼肌或运动发育测试、心脏和呼吸评估以及病史回顾。这些患者还将提供肌活检检查α -糖酐异常

Limb girdle muscular dystrophy 21 (LGMD2I) patients have mutations in fukutin- related protein (FKRP) and present with an unusually wide spectrum of clinical phenotypes. Since the basis for such clinical variability is not yet fully understood, we propose a collaborative project involving patient and complimentary mouse model studies to evaluate the pathogenesis and treatment strategies for LGMD2I. We will define the clinical, molecular and biochemical profiles of patients with LGMD2I to better understand the variability in the clinical presentation of this disorder. Patients with FKRP mutations will undergo annual clinical evaluation, including standardized skeletal muscle or motor development testing, cardiac and respiratory assessment and review of medical history. These patients will also provide a muscle biopsy for alpha-dystroglycan glycosylation analysis, and skin biopsy and blood for mutation confirmation, cell culture and future investigations. In mouse studies we will knockin the FKRP Leu276 to lle mutation, the most common mutation identified in LGMD2I patients. The features of this model will be assessed by behavioral, biochemical and histological analysis of FKRP(L2761/L2761) mice. We will test the hypothesis that the FKRP mutation in mature skeletal and cardiac muscle leads to loss of FKRP expression or activity and, consequently, impaired alpha-dystroglycan interaction with the extracellular matrix. We will also assess the therapeutic potential of FKRP viral-mediated gene transfer in FKRP(L276I/L2761) mice. Finally, based on initial clinical data suggesting an improvement in strength, we will test the hypothesis that steroid treatment alleviates muscle weakness and pathology in FKRP(L276I/L2761) mice. These studies will advance our understanding of LGMD2I clinical phenotypes and the molecular pathogenesis of FKRP muscular dystrophy. Furthermore, this work will enable future therapeutic studies as (a) patient analysis may suggest covariates for therapeutic intervention, (b) potential therapeutic agents may be assessed for viability using the mouse model, and (c) our well-characterized cohort of patients may form the basis for future therapeutic trials.