Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK and National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London.
J Neuropathol Exp Neurol. 2020 Dec 4;79(12):1257-1264. doi: 10.1093/jnen/nlaa120.
Mutations in the fukutin-related protein gene, FKRP, are the most frequent single cause of α-dystroglycanopathy. Rare FKRP mutations are clinically not well characterized. Here, we review the phenotype associated with the rare c.919T>A mutation in FKRP in humans and mice. We describe clinical and paraclinical findings in 6 patients, 2 homozygous, and 4-compound heterozygous for c.919T>A, and compare findings with a mouse model we generated, which is homozygous for the same mutation. In patients, the mutation at the homozygous state is associated with a severe congenital muscular dystrophy phenotype invariably characterized by severe multisystem disease and early death. Compound heterozygous patients have a severe limb-girdle muscular dystrophy phenotype, loss of ambulation before age 20 and respiratory insufficiency. In contrast, mice homozygous for the same mutation show no symptoms or signs of muscle disease. Evidence therefore defines the FKRP c.919T>A as a very severe mutation in humans. The huge discrepancy between phenotypes in humans and mice suggests that differences in protein folding/processing exist between human and mouse Fkrp. This emphasizes the need for more detailed structural analyses of FKRP and shows the challenges of developing appropriate animal models of dystroglycanopathies that mimic the disease course in humans.
FKRP 基因突变是导致α-肌营养不良聚糖病的最常见单一原因。罕见的 FKRP 突变在临床上尚未得到很好的描述。在这里，我们回顾了人类和小鼠中 FKRP 罕见的 c.919T>A 突变相关的表型。我们描述了 6 名患者的临床和临床前发现，其中 2 名纯合子，4 名复合杂合子 c.919T>A，并将这些发现与我们生成的同突变的小鼠模型进行了比较。在患者中，纯合状态下的突变与严重的先天性肌营养不良表型相关，其特征始终是严重的多系统疾病和早期死亡。复合杂合子患者表现为严重的肢带型肌营养不良表型，在 20 岁之前丧失行走能力和呼吸功能不全。相比之下，同样突变的纯合子小鼠没有出现肌肉疾病的任何症状或体征。因此，证据将 FKRP c.919T>A 定义为人类中非常严重的突变。人类和小鼠之间表型的巨大差异表明，人类和小鼠 Fkrp 之间存在蛋白折叠/加工的差异。这强调了对 FKRP 进行更详细结构分析的必要性，并表明了开发模拟人类疾病过程的肌营养不良聚糖病动物模型的挑战。
