Mercimek-Mahmutoglu Saadet, Ndika Joseph, Kanhai Warsha, de Villemeur Thierry Billette, Cheillan David, Christensen Ernst, Dorison Nathalie, Hannig Vickie, Hendriks Yvonne, Hofstede Floris C, Lion-Francois Laurence, Lund Allan M, Mundy Helen, Pitelet Gaele, Raspall-Chaure Miquel, Scott-Schwoerer Jessica A, Szakszon Katalin, Valayannopoulos Vassili, Williams Monique, Salomons Gajja S
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada; Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Hum Mutat. 2014 Apr;35(4):462-9. doi: 10.1002/humu.22511. Epub 2014 Mar 6.
Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.
胍基乙酸甲基转移酶缺乏症（GAMT-D）是一种常染色体隐性遗传的肌酸生物合成障碍疾病。头颅质子磁共振波谱显示肌酸缺乏，以及体液中胍基乙酸水平升高是GAMT-D的生物标志物。在74例患者中，已在GAMT基因中鉴定出50种不同的突变，其中错义变异最为常见。使用问卷从患者的医生处获取错义变异患者的临床和生化特征。在20例患者中，有17种错义变异，25%表现为严重表型，55%为中度表型，20%为轻度表型。利用原发性GAMT-D成纤维细胞过表达这些变异对GAMT酶活性的影响：17种变异未保留显著活性，因此被认为是致病性的。另外两个变异，c.22C>A（p.Pro8Thr）和c.79T>C（p.Tyr27His）（后者在对照队列中检测到）实际上并非致病性的，因为这些等位基因恢复了GAMT酶活性，尽管通过计算机分析预测这两个变异可能具有损害性。我们报告了13例新的GAMT-D患者、6个新突变以及对19种错义变异的功能分析，所有这些都已纳入我们的公共LOVD数据库。我们的功能测定对于确认GAMT基因中已鉴定的错义变异的致病性很重要。
