Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome
Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome
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DOI：
10.1093/hmg/8.4.645
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发表时间：
1999-04-01
影响因子：
3.5
通讯作者：
Friedman, RA
中科院分区：
文献类型：
--
作者：
Johnson, KR;Cook, SA;Friedman, RA
在杰克逊实验室的一群C3 H/HeJ小鼠中发现了一种导致耳聋和盘旋行为的自发突变。突变小鼠的病理学分析显示内耳的大体形态异常，以及畸形或缺失的肾脏。耳聋和异常行为表现为常染色体隐性遗传，并定位于小鼠1号染色体Eya 1基因附近。该基因的人类同源物EYA 1已被证明是鳃-耳-肾（BOR）综合征的基础，BOR是一种常染色体显性遗传疾病，其特征是听力丧失伴相关鳃和肾异常。对突变小鼠Eya 1基因的分子分析显示，在内含子7中插入了脑池内A颗粒（IAP）元件。IAP插入的存在与正常Eya 1信息的表达减少和额外异常转录本的形成有关。如果纯合子而非杂合子的蛋白质水平低于正常发育功能所需的临界阈值，则突变的亚型性质可以解释其隐性遗传。新的小鼠突变被命名为Eya 1（bor），以表示其与人类BOR综合征的相似性，并将为研究突变基因表达和病因学提供有价值的模型。
A spontaneous mutation causing deafness and circling behavior was discovered in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analysis of mutant mice revealed gross morphological abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait and mapped to mouse chromosome 1 near the position of the Eya1 gene. The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. Molecular analysis of the Eya1 gene in mutant mice revealed the insertion of an intracisternal A particle (IAP) element in intron 7, The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. The new mouse mutation is designated Eya1(bor) to denote its similarity to human BOR syndrome, and will provide a valuable model for studying mutant gene expression and etiology.