Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Greenwood Genetic Center, Greenwood, SC, USA.
Hum Mol Genet. 2019 May 1;28(9):1548-1560. doi: 10.1093/hmg/ddy423.
Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) are related heterotetrameric complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a 6-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully assembled GARP and EARP complexes. Likely because of this deficiency, the patient's fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient's fibroblasts exhibits swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.
高尔基相关逆行蛋白 (GARP) 和内体相关再循环蛋白 (EARP) 是相关的异四聚体复合物，分别与高尔基体中间膜囊和再循环内体的胞质面结合。在这些位置，GARP 和 EARP 促进内体衍生的运输载体与相应隔室融合。GARP 和 EARP 共享三个亚基，VPS51、VPS52 和 VPS53，并且每个都有一个额外的复合体特异性亚基，VPS54 或 VPS50。然而，这些复合物在人类生理学中的作用仍然知之甚少。通过外显子组测序，我们在一名 6 岁的严重全面发育迟缓、小头畸形、张力减退、癫痫、皮质视力障碍、桥小脑异常、生长不良、肝功能障碍、下肢水肿和畸形特征的患者中，发现编码共享 GARP/EARP 亚基 VPS51 的基因中存在复合杂合突变。一个等位基因的突变导致移码，产生更长但极不稳定的蛋白质，被蛋白酶体降解。相比之下，另一个突变等位基因产生一个带有单个氨基酸取代的蛋白质，该蛋白质稳定但与其他 GARP/EARP 亚基组装效率较低。因此，来自患者的皮肤成纤维细胞中完全组装的 GARP 和 EARP 复合物水平降低。可能由于这种缺陷，患者的成纤维细胞表现出阳离子非依赖性甘露糖 6-磷酸受体的分布改变，该受体通常将酸性水解酶分拣到溶酶体中。此外，患者的一部分成纤维细胞表现出溶酶体肿胀。这些发现因此确定了一个神经发育障碍的新遗传位点，并强调了 GARP/EARP 功能在细胞和机体生理学中的关键重要性。
