WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome
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DOI：
10.1016/j.ajhg.2017.10.002
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发表时间：
2018-01-04
影响因子：
9.8
通讯作者：
Carvalho, Claudia M. B.
中科院分区：
文献类型：
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作者：
White, Janson J.;Mazzeu, Juliana F.;Carvalho, Claudia M. B.
基因座异质性是多种骨骼发育不良的特征，通常是由于相互作用或重叠的信号通路所致。Robinow综合征是一种历史上难以进行分子诊断的骨骼疾病，可能源于大量的遗传异质性。目前已知的所有致病变异体都存在于非规范的Wnt信号通路中的基因中，包括ROR2、Wnt5A以及最近的DVL1和DVL3。然而，与70%的常染色体显性罗比诺综合征病例一样，分子水平上仍未解决。为了调查这种缺失的遗传性，我们招募了21个家庭，其中至少有一名家庭成员被临床诊断为Robinow或Robinow样表型，并进行了遗传和基因组研究。总共鉴定了四个FZD2变异家系，以及来自两个NXN双等位变异且与表型共分离的两个家庭的三个个体。重要的是，FZD2和NXN都是Wnt5A相互作用组中相关的蛋白质伙伴，支持它们在骨骼发育中的作用。除了证实DVL1和DVL3的聚集性移码变异是导致显性Robinow综合征的主要因素外，我们还在候选基因GPC4和RAC3中发现了可能的致病变异，这两个基因都与Wnt信号通路相关联。这些数据支持了一个初步假设，即Robinow综合征是由Wnt/PCP途径的扰动引起的，提示了相关蛋白的特定相关结构域，并揭示了人类胚胎发育过程中这一信号级联的关键贡献因素。与非等位基因异质性阻碍基因发现的观点相反，这项研究证明了罕见疾病基因组研究在分析人类发育途径中的基因功能方面的作用。
Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, similar to 70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered-1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.