Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
Institute of Human Genetics, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
Am J Hum Genet. 2021 Jun 3;108(6):1151-1160. doi: 10.1016/j.ajhg.2021.04.017. Epub 2021 May 11.
We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing. All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally. Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect, but the clinical features observed in this neurodevelopmental disorder point toward an important but still unknown role of glucose-1,6-bisphosphate or other sugar bisphosphates in brain metabolism.
我们描述了一种由 PGM2L1 缺乏引起的遗传综合征。PGM2 和 PGM2L1 生成己糖-1,6-双磷酸等己糖-1-磷酸，这些物质是糖磷酸变位酶的必需辅因子。这些酶形成 NDP-糖合成和随后的糖基化反应所需的己糖-1-磷酸。虽然 PGM2 在广泛的组织中表达，但 PGM2L1 在大脑中高度表达，导致那里发现的葡萄糖-1,6-双磷酸浓度升高。通过外显子组测序鉴定了 4 名（年龄在 2 至 7.5 岁之间的 3 名女性和 1 名男性）具有 PGM2L1 双等位基因失活突变的个体。这 4 人都有严重的发育和言语迟缓、面部畸形、耳部异常、高拱形腭、斜视、低张力和毛发角化病。3 名个体存在早期肥胖和癫痫发作。对儿童成纤维细胞的分析表明，葡萄糖-1,6-双磷酸和其他糖-1,6-双磷酸显著减少，但仍存在足以最大程度地刺激磷酸变位酶的浓度。因此，NDP-糖的浓度和高度糖基化蛋白 LAMP2 的糖基化正常。与这一点一致的是，受影响个体的血清转铁蛋白正常糖基化。PGM2L1 缺乏似乎不是糖基化缺陷，但在这种神经发育障碍中观察到的临床特征表明，葡萄糖-1,6-双磷酸或其他糖-1,6-双磷酸在大脑代谢中具有重要但仍未知的作用。
