Klomp L W, de Koning T J, Malingré H E, van Beurden E A, Brink M, Opdam F L, Duran M, Jaeken J, Pineda M, Van Maldergem L, Poll-The B T, van den Berg I E, Berger R
Department of Metabolic Diseases, University Medical Center Utrecht, 3584 AE Utrecht, The Netherlands.
Am J Hum Genet. 2000 Dec;67(6):1389-99. doi: 10.1086/316886. Epub 2000 Oct 27.
3-phosphoglycerate dehydrogenase (PHGDH) deficiency is a disorder of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures. To investigate the molecular basis for this disorder, the PHGDH mRNA sequence was characterized, and six patients from four families were analyzed for sequence variations. Five patients from three different families were homozygous for a single nucleotide substitution predicted to change valine at position 490 to methionine. The sixth patient was homozygous for a valine to methionine substitution at position 425; both mutations are located in the carboxyterminal part of PHGDH. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA-blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurological impairment in our patients, the data presented in this paper suggest an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system.
3-磷酸甘油酸脱氢酶（PHGDH）缺乏症是一种L-丝氨酸生物合成障碍疾病，其特征为先天性小头畸形、精神运动发育迟缓及癫痫发作。为探究该疾病的分子基础，对PHGDH mRNA序列进行了特征分析，并对来自四个家族的六名患者进行了序列变异分析。来自三个不同家族的五名患者对于一个预测会将第490位缬氨酸变为甲硫氨酸的单核苷酸替代是纯合的。第六名患者在第425位存在缬氨酸到甲硫氨酸的替代纯合情况；这两个突变均位于PHGDH的羧基末端部分。这些突变蛋白的体外表达导致PHGDH酶活性显著降低。RNA印迹分析表明PHGDH在成人和胎儿脑组织中大量表达。结合我们患者的严重神经功能损害，本文所呈现的数据表明PHGDH活性和L-丝氨酸生物合成在中枢神经系统的代谢、发育和功能中起重要作用。
