Brahimi N, Jambou M, Sarzi E, Serre V, Boddaert N, Romano S, de Lonlay P, Slama A, Munnich A, Rötig A, Bonnefont J P, Lebre A S
AP-HP, Hôpital Necker-Enfants Malades, Département de Génétique, Batiment Lavoisier 3(è) Etage, 149 Rue de Sèvres, Paris F-75015, France.
Mol Genet Metab. 2009 Jul;97(3):221-6. doi: 10.1016/j.ymgme.2009.03.007. Epub 2009 Mar 27.
Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.
脱氧鸟苷激酶（dGK）缺乏是与肝脑表型相关的线粒体DNA耗竭的常见原因。在本研究中，我们描述了DGUOK基因中的一种新的剪接位点突变以及这些DGUOK患者的临床、放射学和遗传学特征。这种新的DGUOK纯合突变（c.444-62C>A）在来自两个北非近亲家庭的三名患者中被鉴定出来，这些患者存在联合呼吸链缺陷和肝脏中线粒体DNA耗竭。文献中报道的DGUOK患者的脑部MRI检查结果正常。有趣的是，我们发现我们的患者中脑桥小脑区域存在异常髓鞘形成，双侧苍白球有中度高信号。这种新突变在第3内含子（位置-62）中产生了一个隐蔽剪接位点，预计会导致产生一种更大的蛋白质，其在阅读框内插入20个氨基酸。对该插入的推定影响进行的计算机模拟分析显示蛋白质构象存在严重冲突：这种插入破坏了dGK激酶结构域的α5螺旋，使该蛋白质无法结合嘌呤脱氧核糖核苷。此外，通过使用跨越4.6 Mb DNA覆盖DGUOK基因座的10个标记（微卫星和单核苷酸多态性）进行单倍型重建，在两个家族中均检测到与疾病共分离的一个常见单倍型。总之，我们报告了一种新的DGUOK剪接位点突变，该突变有助于深入了解一个关键的蛋白质结构域（dGK激酶结构域），并且是北非人群中的首个奠基者突变。
