Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa
Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa
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DOI：
10.1167/iovs.02-0871
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发表时间：
2003-05-01
影响因子：
4.4
通讯作者：
Carballo, M
中科院分区：
文献类型：
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作者：
Martínez-Gimeno, M;Gamundi, MJ;Carballo, M
目的.系统表达的前mRNA剪接因子基因PRPF 3、PRPF 8和PRPF 31的突变最近被认为与常染色体显性视网膜色素变性（adRP）有关。本研究旨在鉴定150个受adRP影响的西班牙家族中PRPF 3、PRPF 8和PRPF 31的突变，测量这些基因突变对该人群adRP的贡献，并将RP表型表达与前mRNA剪接因子基因突变相关联。变性梯度凝胶电泳（DGGE）和直接基因组测序被用来评估完整的，编码区和侧翼内含子序列的PRPF 31基因，外显子42的PRPF 8，和外显子11的PRPF 3的突变在150个无关的索引患者adRP。RP患者及其亲属的眼科和电生理检查是根据先前的协议进行的。三个由插入和缺失序列引起的无义突变和两个错义突变。在5例不相关的杂合子患者中检测到PRPF 8基因终止密码子内（Arg 2310 Gly）和终止密码子内（TGA->TTG）。3例患者为PRPF 31基因第8外显子不同无义突变的杂合子携带者，在PRPF 3基因第11外显子发现一个Thr 494 Met突变。观察到PRPF 8和PRPF 3中的突变与adRP共分离。但在两个家系中检测到的两个引起adRP的PRPF 31无义突变均为无症状携带者。在西班牙人群中发现了导致adRP的前mRNA剪接因子基因PRPF 3、PRPF 8和PRPF 31中的9个突变，其中6个是新的。在与引起adRP的其他基因中发现的突变相关的校正后，它们对adRP的贡献约为5%。携带前mRNA剪接因子PRPF 8基因突变的患者表现为I型弥漫性RP。PRPF 31基因无义突变的无症状携带者的存在表明这些突变在家庭中的不完全传播。
PURPOSE. Mutations in the systemically expressed pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 have recently been associated with autosomal dominant retinitis pigmentosa (adRP). This study was intended to identify mutations in PRPF3, PRPF8, and PRPF31 in 150 Spanish families affected by adRP, to measure the contribution of mutations in these genes to adRP in that population, and to correlate RP phenotype expression with mutations in pre-mRNA splicing-factor genes.METHODS. Denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing were used to evaluate the complete, coding region and flanking intronic sequences of the PRPF31 gene, exon 42 of PRPF8, and exon 11 of PRPF3 for mutations in 150 unrelated index patients with adRP. Ophthalmic and electrophysiological examination of patients with RP and their relatives was performed according to preexisting protocols.RESULTS. Three nonsense mutations caused by insertion and deletion Sequences and two missense mutations. (Arg2310Gly) and within the stop codon of the PRPF8 gene (TGA-->TTG), were detected in five unrelated heterozygous patients. Three patients were heterozygous carriers of different nonsense mutations in exon 8 of the PRPF31, gene and one Thr494Met mutation was found in exon 11 of the PRPF3 gene. Cosegregation of the mutation in PRPF8 and PRPF3 with adRP was observed. However, two nonsense mutations in PRPF31 causing adRP detected in two families showed asymptomatic carriers.CONCLUSIONS. Nine mutations, six of which are novel, in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31, causing adRP have been identified in the Spanish population. Their contribution to adRP is approximately 5% after correction in relation to mutations found in other genes causing adRP. The patients carrying a mutation in the pre-mRNA splicing-factor PRPF8 gene showed a type I diffuse RP. The existence of asymptomatic carriers of the nonsense mutation in the PRPF31 gene suggests incomplete penetrance for these mutations in the families.