Deletions and loss-of-function variants in TP63 associated with orofacial clefting
Deletions and loss-of-function variants in TP63 associated with orofacial clefting
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DOI：
10.1038/s41431-019-0370-0
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发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
van Bokhoven, Hans
中科院分区：
文献类型：
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作者：
Khandelwal, Kriti D.;van den Boogaard, Marie-Jose H.;van Bokhoven, Hans
我们的目标是识别与口面裂（OFC）相关的TP 63的新型缺失和变体。使用微阵列分析在三个OFC家族中评估拷贝数变异。随后，我们使用分子倒置探针（MIP）分析了1072名OFC患者和706名基于人群的对照组中的TP63。我们确定了部分缺失TP63的个人从三个家庭受影响的OFC。在OFC队列中，我们鉴定了几种预测引起功能丧失等位基因的TP63变体，包括移码变体c.569_576del（p.（Ala190Aspfs*5））和无义变体c.997C>T（p.（Gln333*）），其在DNA结合结构域中引入提前终止密码子。此外，我们鉴定了寡聚化结构域c.1213G>A中的第一个错义变体（p.（Val405Met）），这发生在OFC的个人。这种变体被证明可以消除突变型p63蛋白寡聚化成寡聚复合物，因此可能代表功能丧失等位基因，而不是显性阴性等位基因。所有这些变异都是从未受影响的亲本遗传的，这表明这些功能丧失的等位基因的突变率降低。我们的数据表明，TP63中的功能缺失等位基因也可以引起OFC作为主要表型。我们已经发现了p63的剂量依赖性功能，这是以前拒绝。
We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.