LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome
LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome
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DOI：
10.1016/j.ajhg.2010.03.004
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发表时间：
2010-05-14
影响因子：
9.8
通讯作者：
Wollnik, Bernd
中科院分区：
文献类型：
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作者：
Li, Yun;Pawlik, Barbara;Wollnik, Bernd
Cenani-Lenz综合征（CLS）是一种影响远端肢体发育的常染色体隐性遗传性先天性疾病。其主要特征是并指和/或少指，现在显示通常与肾脏异常有关。我们使用了纯合性定位的方法来映射的CLS 1基因座染色体11p11.2-q13.1。通过对候选基因进行测序，我们在12个CLS家系中发现了隐性LRP 4突变。LRP 4属于低密度脂蛋白（LDL）受体相关蛋白（LRP），其在各种发育过程中至关重要。已知LRP 4拮抗LRP 6介导的经典Wnt信号传导的激活，这是一种因鉴定的突变而丧失的功能。我们的发现增加了与异常脂蛋白受体依赖性信号相关的先天性异常的范围。
Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is now shown to be commonly associated with kidney anomalies. We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. Our findings increase the spectrum of congenital anomalies associated with abnormal lipoprotein receptor-dependent signaling.