A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations.
A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations.
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DOI：
10.1186/1750-1172-8-84
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发表时间：
2013-06-13
影响因子：
3.7
通讯作者：
Newman WG
中科院分区：
文献类型：
--
作者：
Banka S;Newman WG
G6 PC 3基因编码广泛表达的葡萄糖-6-磷酸酶（G-6-β-磷酸酶或G-6-β-磷酸酶3或G6 PC 3）。双等位基因G6 PC 3突变导致G6 PC 3缺乏的多系统常染色体隐性遗传病（也称为4型重度先天性中性粒细胞减少症，MIM 612541）。迄今为止，文献中至少描述了57例G6 PC 3缺陷患者。G6 PC 3缺乏症的特征在于严重的先天性中性粒细胞减少症、复发性细菌感染、许多患者中的间歇性血小板减少症、突出的浅静脉模式以及先天性心脏缺陷和泌尿生殖器异常的高发病率。该病症的表型谱很广，包括罕见的表现，如骨髓谱系的成熟停滞、正常细胞骨髓、骨髓细胞增生、淋巴细胞减少、胸腺发育不全、炎症性肠病、原发性肺动脉高压、内分泌异常、生长迟缓、轻微面部畸形、骨骼和皮肤异常等。Dursun综合征是这种扩展谱的一部分。G6 PC 3缺陷也可导致孤立的非综合征性重度中性粒细胞减少症。G6 PC 3突变导致酶活性降低、内质网应激反应、受影响细胞的凋亡率增加和中性粒细胞活性功能障碍。在这篇综述中，我们证明错义G6 PC 3突变的功能丧失可能是由于酶稳定性降低。这种情况可以通过G6 PC 3基因测序来诊断。许多G6 PC 3创始人突变在不同人群中是已知的，也存在可能的基因型-表型关系。G6 PC 3缺陷应被视为任何不明原因的先天性中性粒细胞减少症患者的鉴别诊断的一部分。G-CSF治疗可改善中性粒细胞数量，预防感染并改善生活质量。轻度感染的患者可以使用预防性抗生素进行管理。未经治疗的G6 PC 3缺乏症可能是致命的。在所有疑似或确诊G6 PC 3缺乏症的病例中，应进行超声心动图、肾脏和盆腔超声扫描。常规评估应包括生化特征、生长特征和静脉曲张或静脉溃疡发展的监测。
The G6PC3 gene encodes the ubiquitously expressed glucose-6-phosphatase enzyme (G-6-Pase β or G-6-Pase 3 or G6PC3). Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency (also called severe congenital neutropenia type 4, MIM 612541). To date, at least 57 patients with G6PC3 deficiency have been described in the literature. G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies. The phenotypic spectrum of the condition is wide and includes rare manifestations such as maturation arrest of the myeloid lineage, a normocellular bone marrow, myelokathexis, lymphopaenia, thymic hypoplasia, inflammatory bowel disease, primary pulmonary hypertension, endocrine abnormalities, growth retardation, minor facial dysmorphism, skeletal and integument anomalies amongst others. Dursun syndrome is part of this extended spectrum. G6PC3 deficiency can also result in isolated non-syndromic severe neutropenia. G6PC3 mutations in result in reduced enzyme activity, endoplasmic reticulum stress response, increased rates of apoptosis of affected cells and dysfunction of neutrophil activity. In this review we demonstrate that loss of function in missense G6PC3 mutations likely results from decreased enzyme stability. The condition can be diagnosed by sequencing the G6PC3 gene. A number of G6PC3 founder mutations are known in various populations and a possible genotype-phenotype relationship also exists. G6PC3 deficiency should be considered as part of the differential diagnoses in any patient with unexplained congenital neutropenia. Treatment with G-CSF leads to improvement in neutrophil numbers, prevents infections and improves quality of life. Mildly affected patients can be managed with prophylactic antibiotics. Untreated G6PC3 deficiency can be fatal. Echocardiogram, renal and pelvic ultrasound scans should be performed in all cases of suspected or confirmed G6PC3 deficiency. Routine assessment should include biochemical profile, growth profile and monitoring for development of varicose veins or venous ulcers.
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