GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.
GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.
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DOI：
10.3390/ijms18020240
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发表时间：
2017-01-25
影响因子：
5.6
通讯作者：
Vanakker OM
中科院分区：
文献类型：
--
作者：
De Vilder EY;Debacker J;Vanakker OM
γ -羧化由γ -谷氨酰羧化酶（GGCX）进行，是激活维生素k依赖性蛋白（VKDP）所必需的酶促过程，在各种生物过程中具有重要功能。编码GGCX基因的突变与多种表型相关，其中维生素k依赖性凝血因子缺乏症（VKCFD1）最为人所知。其他患者有皮肤、眼睛、心脏或骨骼表现。由于基因型-表型相关性从未被描述过，我们系统地回顾了文献，寻找至少有一个具有表型描述的GGCX突变的患者，结果有47例患者。虽然这一数字太低，不足以形成有效的统计相关性——这是孤儿病中常见的问题——但我们证明了水平转移的跨膜结构域在心脏和骨骼表现中的关键作用。此外，自然历史表明，衰老是皮肤和眼睛症状的主要决定因素。VKCFD1症状在同一蛋白结构域具有两种突变的患者中似乎更严重，尽管这与凝血因子功能更受干扰无关。最后，不同的GGCX功能域可能专门用于非常特定的VKDP的羧化。综上所述，本系统综述提示ggcx相关表型确实可能存在基因型-表型相关性，可以指导患者的咨询和管理。
Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.