A novel APC mutation defines a second locus for Cenani-Lenz syndrome
A novel APC mutation defines a second locus for Cenani-Lenz syndrome
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DOI：
10.1136/jmedgenet-2014-102850
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
--
作者：
Patel, Nisha;Faqeih, Eissa;Alkuraya, Fowzan S.
Cenani-Lenz综合征（CLS）是一种常染色体隐性遗传疾病，以独特的并指（趾）畸形、肾发育不全和面部畸形为特征。LRP 4突变被确定在大多数，但不是所有的患者与此syndrome，表明存在至少一个额外的locus.Materials和方法的临床特征的一个新的CLS家庭，然后由自身接合性映射，全外显子组测序和全球基因表达profiling.Results我们描述了一个扩展的近亲沙特家庭的典型CLS功能，除了显着的脊柱侧凸。该家族中的疾病映射到5q22.2上的单个纯合子间隔，其中全外显子组测序揭示了APC中存在新的剪接突变，其导致野生型转录物减少约80%，并产生预测严重截短的APC的异常转录物。这被发现与上调Wnt/β-catenin signaling.Conclusions在一个模式类似LRP 4突变预测如何否定蛋白质的拮抗作用Wnt/β-catenin信号，我们建议，减少APC可能会增加β-catenin凭借受损的降解，导致类似的表型结果的可用性。这是APC首次与人类表型相关联，而这种表型与其在肿瘤学中的既定作用不同。
Background Cenani-Lenz syndrome (CLS) is an autosomal recessive condition characterised by a unique pattern of syndactyly, and variable penetrance of renal agenesis and facial dysmorphism. LRP4 mutations were identified in most, but not all patients with this syndrome, suggesting the presence of at least one additional locus.Materials and methods Clinical characterisation of a new CLS family followed by autozygosity mapping, whole-exome sequencing and global gene expression profiling.Results We describe an extended consanguineous Saudi family with typical CLS features in addition to significant scoliosis. The disease in this family maps to a single autozygous interval on 5q22.2, in which whole-exome sequencing revealed the presence of a novel splicing mutation in APC that results in similar to 80% reduction of the wild-type transcript and the creation of an aberrant transcript that predicts a severely truncated APC. This was found to be associated with upregulation of Wnt/beta-catenin signalling.Conclusions In a pattern similar to how LRP4 mutations are predicted to negate the protein's antagonistic effect on Wnt/beta-catenin signalling, we propose that reduction of APC may increase the availability of beta-catenin by virtue of impaired degradation, leading to a similar phenotypic outcome. This is the first time APC is linked to a human phenotype distinct from its established role in oncology.