Rosenfeld P J, Hahn L B, Sandberg M A, Dryja T P, Berson E L
Berman-Gund Laboratory for the Study of Retinal Degenerations, Boston, Massachusetts, USA.
Invest Ophthalmol Vis Sci. 1995 Oct;36(11):2186-92.
To determine whether a rhodopsin splice donor site mutation at the 5' end of intron 4 is a cause of autosomal dominant retinitis pigmentosa.
Heterozygous carriers of the same rhodopsin splice site mutation in two pedigrees were identified using single-strand conformation polymorphism analysis. Twelve heterozygous carriers were evaluated by ophthalmoscopy. Goldmann kinetic visual fields, dark adaptation thresholds, and full-field electroretinograms including rod intensity-response functions. Clinical findings from the heterozygous carriers of the splice site mutation were compared with those from heterozygous carriers from a separate family with a known recessive rhodopsin null mutation, Glu249X.
Analysis of DNA from 48 members of two pedigrees revealed 25 heterozygous carriers of the splice site mutation, ranging in age from 14 to 82 years. There were no homozygotes with the rhodopsin splice site mutation. Of the 25 heterozygous carriers, 24 were asymptomatic. Eleven asymptomatic heterozygotes were examined, including four older than 65 years of age. They were found to have normal fundi, full visual fields, and slightly elevated final rod dark adaptation thresholds. Their rod electroretinographic b-wave amplitudes were slightly diminished over the full range of blue light intensities. Rod a-wave implicit times were slightly but significantly prolonged in response to the brightest blue flash of light. These subtle abnormalities in rod function were similar to those found in asymptomatic heterozygous carriers of the recessive Glu249X mutation. Only one of the 25 heterozygous carriers of the splice site mutation had symptoms and signs of retinitis pigmentosa.
Because 96% of these heterozygous carriers do not have retinitis pigmentosa, it is unlikely that this mutation in intron 4 is a dominant allele. The subtle abnormalities of rod function found in asymptomatic carriers are similar to those found in heterozygous carriers of a recessive rhodopsin allele. The one heterozygous carrier with retinitis pigmentosa probably has a second mutation in the rhodopsin gene or has a defect or defects in another gene that causes his disease.
确定内含子4 5′端的视紫红质剪接供体位点突变是否为常染色体显性遗传性视网膜色素变性的病因。
使用单链构象多态性分析在两个家系中鉴定出同一视紫红质剪接位点突变的杂合子携带者。通过检眼镜检查对12名杂合子携带者进行评估。包括杆体强度-反应函数的Goldmann动态视野、暗适应阈值和全视野视网膜电图。将剪接位点突变杂合子携带者的临床发现与来自另一个具有已知隐性视紫红质无义突变Glu249X家系的杂合子携带者的临床发现进行比较。
对两个家系的48名成员的DNA分析显示，有25名剪接位点突变的杂合子携带者，年龄在14至82岁之间。没有视紫红质剪接位点突变的纯合子。在25名杂合子携带者中，24名无症状。检查了11名无症状杂合子，包括4名年龄超过65岁的。发现他们眼底正常、视野完整，最终杆体暗适应阈值略有升高。在整个蓝光强度范围内，他们的杆体视网膜电图b波振幅略有降低。对最亮的蓝色闪光刺激，杆体a波的隐含时间略有但显著延长。这些杆体功能的细微异常与隐性Glu249X突变的无症状杂合子携带者中发现的异常相似。25名剪接位点突变杂合子携带者中只有1名有视网膜色素变性的症状和体征。
由于这些杂合子携带者中有96%没有视网膜色素变性，因此内含子4中的这种突变不太可能是显性等位基因。在无症状携带者中发现的杆体功能细微异常与隐性视紫红质等位基因杂合子携带者中发现的异常相似。那名患有视网膜色素变性的杂合子携带者可能在视紫红质基因中有第二个突变，或者在另一个导致其疾病的基因中有一个或多个缺陷。
