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一种影响视网膜母细胞瘤肿瘤抑制基因第23内含子剪接的新型基因组成突变导致pRB活性部分丧失。

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity.

作者信息

Sánchez-Sánchez Francisco, Kruetzfeldt Maja, Nájera Carmen, Mittnacht Sibylle

机构信息

Departamento de Genética, Facultad de Ciencias Biológicas, Universidad de Valencia, Burjassot, Valencia, Spain.

出版信息

Hum Mutat. 2005 Feb;25(2):223. doi: 10.1002/humu.9305.

Abstract

Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past.

摘要

视网膜母细胞瘤的遗传易感性是由RB1基因的种系突变引起的。对受影响个体进行遗传咨询并为其家族进行准确的风险预测需要识别致病突变。此外,突变的性质可以决定遗传外显率、疾病表现和预后。我们在此描述并对功能进行表征,该新型RB1突变等位基因存在于一名散发性双侧视网膜母细胞瘤患者的种系中。该突变产生一个有效的剪接受体位点,导致预测的蛋白质产物从其羧基末端缺失81个氨基酸。我们证明异常剪接的转录本大量存在于患者的外周血中,并提供证据表明预测的蛋白质产物显示出部分活性丧失,在程度和表现上反映了部分外显的RB1错义突变体R661W的情况。这意味着携带该突变的个体可能会出现表达降低和不完全外显的疾病,并预测过去散发病例中发现的类似突变也会有这样的表现。

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