Celeste Frank V, Vilboux Thierry, Ciccone Carla, de Dios John Karl, Malicdan May Christine V, Leoyklang Petcharat, McKew John C, Gahl William A, Carrillo-Carrasco Nuria, Huizing Marjan
Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
Hum Mutat. 2014 Aug;35(8):915-26. doi: 10.1002/humu.22583.
The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ∼4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials.
GNE基因编码唾液酸生物合成的限速双功能酶，即尿苷二磷酸-N-乙酰葡糖胺2-表异构酶/N-乙酰甘露糖胺激酶（GNE）。双等位基因GNE突变是成人起病的进行性肌病——GNE肌病的病因。与GNE肌病相关的GNE突变主要为错义突变，导致GNE酶活性降低，但并非完全缺失。GNE肌病的确切发病机制尚不清楚，但可能涉及异常（肌肉）唾液酸化。在此，我们总结了154个已报道的和新发现的与GNE肌病相关的GNE变异体，包括122个错义变异体、11个无义变异体、14个插入/缺失变异体和7个内含子变异体。所有变异体都存于在线GNE变异数据库（http://www.dmd.nl/nmdb2/home.php?select_db=GNE）中。我们报告了所有变异体对蛋白质功能的预测影响以及所选变异体对表异构酶和/或激酶酶活性的预测影响。通过分析外显子序列数据库，我们鉴定出三个常见的、未报道的GNE错义变异体/多态性，这对未来的序列解读很重要。基于等位基因频率，我们估计GNE肌病在全球的患病率约为4-21/1,000,000。这种此前未被认识到的高患病率证实了许多患者可能未被诊断的怀疑。医生对GNE肌病的认识对于识别新患者至关重要，这对于更好地理解该疾病的发病机制以及正在进行的治疗试验的成功都是必要的。
