WDR34 Mutations that Cause Short-Rib Polydactyly Syndrome Type III/Severe Asphyxiating Thoracic Dysplasia Reveal a Role for the NF-κB Pathway in Cilia
WDR34 Mutations that Cause Short-Rib Polydactyly Syndrome Type III/Severe Asphyxiating Thoracic Dysplasia Reveal a Role for the NF-κB Pathway in Cilia
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DOI：
10.1016/j.ajhg.2013.10.007
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发表时间：
2013-11-07
影响因子：
9.8
通讯作者：
Cormier-Daire, Valerie
中科院分区：
文献类型：
--
作者：
Huber, Celine;Wu, Sulin;Cormier-Daire, Valerie
短肋多指（SRP）综合征III型，或Verma-Naumoff综合征，是一种常染色体隐性软骨发育不良，其特征为短肋骨、窄胸、短长骨、异常髋臼和许多外骨骼畸形，在围产期是致命的。目前，已经鉴定出两个基因（IFFT 80和DYNC 2 H1）的突变是导致SPY III型的原因。通过在三个受影响的兄弟姐妹中进行纯合性作图，在染色体9q34.11上确定了该疾病的基因座，并且在三个独立的家庭中发现了WDR 34中三个错义突变的纯合性，以及一个家庭中突变的复合杂合性。WDR 34编码具有5个WD 40结构域的WD重复蛋白家族的成员，其充当IL-1 R/TLR 3/TLR 4诱导的NF-κ B活化途径的TAK 1相关抑制剂。通过结构建模，我们发现三个突变中的两个改变了WDR 34的特定结构域。我们发现WDR 34突变体成纤维细胞的初级纤毛明显短于正常，并有一个球根状的尖端。本报告扩大了SPY III型的发病机制，并表明NF-κ B活化途径的调节剂参与骨骼纤毛病变的发病机制。
Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SPY type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-kappa B activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SPY type III and demonstrates that a regulator of the NF-kappa B activation pathway is involved in the pathogenesis of the skeletal ciliopathies.