Sass Jorn Oliver, Mohr Verena, Olbrich Heike, Engelke Udo, Horvath Judit, Fliegauf Manfred, Loges Niki Tomas, Schweitzer-Krantz Susanne, Moebus Ralf, Weiler Polly, Kispert Andreas, Superti-Furga Andrea, Wevers Ron A, Omran Heymut
Department of General Pediatrics and Adolescent Medicine, University Children's Hospital Freiburg, Freiburg, Germany.
Am J Hum Genet. 2006 Mar;78(3):401-9. doi: 10.1086/500563. Epub 2006 Jan 18.
N-terminal acetylation of proteins is a widespread and highly conserved process. Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses.
蛋白质的N端乙酰化是一个广泛存在且高度保守的过程。氨基酰化酶1（ACY1；EC 3.5.14）是氨基酰化酶中含量最丰富的一种，这类酶参与N - 乙酰化蛋白质的水解。在此，我们报告了4名ACY1基因缺陷的儿童。他们是通过气相色谱 - 质谱联用的有机酸分析被识别出来的，结果显示几种N - 乙酰化氨基酸的尿排泄增加，包括蛋氨酸、谷氨酸、丙氨酸、亮氨酸、甘氨酸、缬氨酸和异亮氨酸的衍生物。尿液样本的核磁共振光谱分析检测到一种独特的N - 乙酰化代谢物模式，与ACY1功能障碍一致。对患者淋巴母细胞的功能分析证实了ACY1缺陷。突变分析在所有4名受影响个体中发现了隐性功能丧失或错义ACY1突变。我们得出结论，这些儿童中的ACY1突变导致了功能性ACY1缺陷和N - 乙酰化氨基酸的排泄。然而，关于ACY1缺陷的临床意义仍存在疑问。这些ACY1缺陷个体是由于非特异性精神运动发育迟缓（1例）、伴有小脑蚓部萎缩和脊髓空洞症的精神运动发育迟缓（1例）、明显的肌张力低下（1例）以及对早期治疗的生物素酶缺乏症的随访且临床检查结果正常（1例）而通过尿液代谢筛查确定的。由于ACY1在鱼类、青蛙、小鼠和人类中具有进化保守性，且在人类中枢神经系统（CNS）中表达，因此可以设想它在CNS功能或发育中起作用，但尚未得到证实。因此，在这一点上，我们无法确定ACY1缺陷是具有多效性临床表型的致病意义，还是仅仅是一种生化变异。认识到这种新的遗传实体可能有助于明确其临床意义并避免错误诊断。
