Pillers D A, Fitzgerald K M, Duncan N M, Rash S M, White R A, Dwinnell S J, Powell B R, Schnur R E, Ray P N, Cibis G W, Weleber R G
Department of Pediatrics, Oregon Child Health Research Center, Doernbecher Children's Hospital, Oregon Health Sciences University, Portland 97201-3042, USA.
Hum Genet. 1999 Jul-Aug;105(1-2):2-9. doi: 10.1007/s004399900111.
The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3' defects have a phenotype similar to that seen in DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5' of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5' of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.
杜兴氏和贝克氏肌营养不良症（DMD/BMD）患者的暗适应视网膜电图（ERG）显示b波振幅显著降低。DMD小鼠模型的基因型-表型研究表明，突变对表型具有位置特异性影响：肌营养不良蛋白5'端缺陷的小鼠ERG正常，中央区域缺陷的小鼠b波振幅正常，但b波和振荡电位的隐含时间延长，而3'端缺陷的小鼠具有与DMD/BMD患者相似的表型。小鼠研究表明，羧基末端肌营养不良蛋白异构体Dp260在视网膜电生理学中起关键作用。我们通过临床检查和文献回顾对DMD/BMD患者进行了系统评估，以确定小鼠中观察到的突变位置特异性影响在人类中是否存在。我们发现，在人类中，DMD缺陷的更广泛变异与b波振幅降低相关。ERG正常的个体突变主要位于Dp260转录起始位点的5'端。我们的结果表明，ERG b波表型中最重要的决定因素是突变位置，而非肌肉疾病严重程度。Dp260转录起始位点5'端有突变的患者中，46%的ERG异常，而远端突变患者的这一比例为94%。人类基因型-表型相关性与Dp260在正常视网膜电生理学中的作用一致，也可能反映了其他C端肌营养不良蛋白异构体的表达及其对视网膜信号传递的贡献。
