Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1
Renate ZeevaertFrançois FoulquierBoyan DimitrovEllen ReyndersRita Van Damme‐LombaertsE SimeonovWillem AnnaertGert MatthijsJ. Jaeken
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We describe two patients with a cerebrocostomandibular-like syndrome and a novel mutation in conserved oligomeric Golgi (COG) subunit 1, one of the subunits of the conserved oligomeric Golgi complex. This hetero-octameric protein complex is involved in retrograde vesicular trafficking and glycosylation. We identified in both patients an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7. Real-time reverse transcriptase polymerase chain reaction showed in the first patient only 3% of normal transcript when compared with control. A delay in retrograde trafficking could be demonstrated by Brefeldin A treatment of this patient's fibroblasts. The costovertebral dysplasia of the two patients has been described in cerebrocostomandibular syndrome (CCMS), but also in cerebrofaciothoracic dysplasia and spondylocostal dysostosis. CCMS itself is heterogeneous because both autosomal dominant and autosomal recessive inheritance has been described. We anticipate further genetic heterogeneity because no mutations in COG1 were found in two additional patients with a CCMS.Keywords:
Brefeldin A
Summary— The effects of the drug Brefeldin A, shown to block the translocation of proteins between the endoplasmic reticulum and the Golgi apparatus in animal cells, were studied on different plant cell systems. In suspension culture cells and root tissues, the Golgi aparatus was affected by Brefeldin A treatments resulting in distortion and dissociation of the Golgi stacks, coupled with appearance of numerous vesicles in the cytoplasm. This process was reversible. Therefore, Brefeldin A provides a powerful tool with which to study Golgi dynamics and function in plant as well as in animal cells.
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N ‐Ethylmaleimide‐sensitive factor (NSF) is required for multiple pathways of vesicle‐mediated protein transport. Microinjection of a monoclonal anti‐NSF antibody almost completely blocked brefeldin A‐promoted Golgi disassembly without affecting the rapid release of β‐COP, a subunit of the Golgi coat proteins (COPI), from the Golgi apparatus. Similar results were obtained using a dominant‐negative NSF which is known to compete with endogenous NSF. The present results suggest that an NSF‐mediated step is present in the brefeldin A‐promoted disassembly of the Golgi apparatus.
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Brefeldin A (BFA) has a profound effect on the structure of the Golgi apparatus, causing Golgi proteins to redistribute into the ER minutes after drug treatment. Here we describe the dissociation of a 110-kD cytoplasmically oriented peripheral membrane protein (Allan, V. J., and T. E. Kreis. 1986. J. Cell Biol. 103:2229-2239) from the Golgi apparatus as an early event in BFA action, preceding other morphologic changes. In contrast, other peripheral membrane proteins of the Golgi apparatus were not released but followed Golgi membrane into the ER during BFA treatment. The 110-kD protein remained widely dispersed throughout the cytoplasm during drug treatment, but upon removal of BFA it reassociated with membranes during reformation of the Golgi apparatus. Although a 30-s exposure to the drug was sufficient to cause the redistribution of the 110-kD protein, removal of the drug after this short exposure resulted in the reassociation of the 110-kD protein and no change in Golgi structure. If cells were exposed to BFA for 1 min or more, however, a portion of the Golgi membrane was committed to move into and out of the ER after removal of the drug. ATP depletion also caused the reversible release of the 110-kD protein, but without Golgi membrane redistribution into the ER. These findings suggest that the interaction between the 110-kD protein and the Golgi apparatus is dynamic and can be perturbed by metabolic changes or the drug BFA.
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ABSTRACT The fungal fatty acid derivative Brefeldin A (BFA), has been used to study the reversible distribution of a Golgi glycoprotein, the JIM 84 epitope, into the cytosol of higher plant cells. Treatment of both maize and onion root tip cells resulted in a rearrangement of the Golgi stacks into either circular formations or a perinuclear distribution. The Golgi cisternae became curved and vesiculated and in cells where the Golgi apparatus was totally dispersed the JIM 84 epitope was associated with large areas in the cytosol which were also vesiculated. On removal of the BFA the Golgi apparatus reformed and the JIM 84 epitope was again located in the cisternal stacks. This mode of BFA action is compared with that so far described for animal cells.
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Golgi apparatus changes start at 90 to 120 seconds following to the onset of Brefeldin A (BFA)-administration and after coated regions had already disappeared at 30 to 60 seconds. The Golgi apparatus stacks disassemble and long tubules grow out of the Golgi region. After 3 to 5 min, a Golgi apparatus is missing in the cells and instead, the cytoplasm is occupied by a network of membrane tubules being interwoven with membranes of the endoplasmic reticulum. At places, glomerular membrane figures form conspicuous "organelles" in BFA-treated cells (cf. Figs. 39 and 40).
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Journal Article Brefeldin A-induced disassembly of the Golgi apparatus is followed by disruption of the endoplasmic reticulum in plant cells Get access Janey Henderson, Janey Henderson 4 1School of Biological and Molecular Sciences, Oxford Brookes UniversityGipsy Lane Campus, Oxford OX3 OBP, UK 4 To whom correspondence should be addressed. Fax:+44 865 483955 Search for other works by this author on: Oxford Academic PubMed Google Scholar Béatrice Stiat-Jeunemaitre, Béatrice Stiat-Jeunemaitre 1School of Biological and Molecular Sciences, Oxford Brookes UniversityGipsy Lane Campus, Oxford OX3 OBP, UK2Physiologie Cellulaire et Moléculaire des Plantes, CNRS, URA 1180, UniversitéPierre et Marie Curie, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Napier, Richard Napier 3Horticulture Research InternationalEast Malling, Kent ME19 6BJ, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Chris Hawes Chris Hawes 1School of Biological and Molecular Sciences, Oxford Brookes UniversityGipsy Lane Campus, Oxford OX3 OBP, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Experimental Botany, Volume 45, Issue 10, October 1994, Pages 1347–1351, https://doi.org/10.1093/jxb/45.10.1347 Published: 01 October 1994 Article history Received: 22 April 1994 Accepted: 20 June 1994 Published: 01 October 1994
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在植物房间， Golgi 仪器由接着，由有清楚的 cis-to-trans 极性的几弄平的 cisternae 构成的众多的栈组成。在在生活房间以内的正常工作期间，这个不平常的细胞器显示象整个栈活动性，通过 cisternae 的经常的膜流动，和通过 ER 再循环的 Golgi 酶那样的大量动态行为。为了进一步调查 Golgi 的各种各样的方面，叠动力学和正直，我们共同表示在烟草 BY-2 房间确定的 Golgi 标记配对在导致的 monensin 处理，运动，和 brefeldin A (BFA ) 期间区分 Golgi 的亚分隔空间拆卸。当他们通过细胞质移动， cis 和 trans 标记的联合表明 Golgi 栈仍然保持未经触动。在这些期间，运动显示出的 Golgi 栈取向为向前移动的 cis 方面的细微偏爱，而是 trans cisternae 也在前缘被发现。在 BFA 处理期间，不同亚分隔空间关于顺序与 ER 一起熔化的观察的栈的一半；然而，没有一致顺序能被检测。相反，当中间时， ionophore monensin 导致了 trans cisternae 胀大并且特别地 cis cisternae 主要是未受影响的。我们的结果因此与 ER 一起关于运动和导致 BFA 的熔化表明不同 cisternae 的一个显著等价。另外，我们建议双标签的荧光显微镜学和药处理的联合能提供一条简单其他的途径给蛋白质本地化的决心到特定的 Golgi 亚分隔空间。
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Human autoantibodies offer unique tools for the study of cellular constituents since they usually recognize highly conserved components, the most difficult to detect due to their low immunogenicity. The serum from a patient with Sjögren's syndrome (RM serum) showing a very high reactivity to the Golgi complex has been shown to immunoprecipitate and to immunodetect by Western blotting experiments a protein mol wt 210,000 (p210) that was shown to be peripheral and cytoplasmically disposed. A close examination of the p210 labeling revealed some differences with Golgi markers: RM serum staining was slightly more extensive than several Golgi markers and showed a discontinuous or granular appearance. Nocodazole induced a specific and early segregation of many p210-associated vesicles or tubules from Golgi apparatus. Upon brefeldin A treatment, p210 did not redistribute in the ER as did other Golgi proteins. In contrast, it exhibited a vesicular pattern reminiscent to that displayed by proteins residing in the intermediate compartment. Double staining immunofluorescence using the RM serum and the marker of the intermediate compartment, p58, revealed segregation of both proteins in control conditions but colocalization in BFA-treated cells. We have further demonstrated by combining different drug treatments that p210-containing elements in brefeldin A-treated cells belong indeed to the intermediate compartment. Experiments on brefeldin A recovery suggested that these p210 elements might play a role in reformation and repositioning of the Golgi apparatus. Ultrastructural localization performed by immunoperoxidase staining allowed us to establish that p210 interacted with the external side of an abundant tubulo-vesicular system on the cis side of the Golgi complex which extended to connecting structures and vesicles between saccules or stacks of cisternae, p210 appears to be a novel protein residing in the cis-Golgi network that may cycle between the Golgi apparatus and the intermediate compartment.
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The Golgi apparatus forms stacks of cisternae in many eukaryotic cells. However, little is known about how such a stacked structure is formed and maintained. To address this question, plant cells provide a system suitable for live-imaging approaches because individual Golgi stacks are well separated in the cytoplasm. We established tobacco BY-2 cell lines expressing multiple Golgi markers tagged by different fluorescent proteins and observed their responses to brefeldin A (BFA) treatment and BFA removal. BFA treatment disrupted cis, medial, and trans cisternae but caused distinct relocalization patterns depending on the proteins examined. Medial- and trans-Golgi proteins, as well as one cis-Golgi protein, were absorbed into the endoplasmic reticulum (ER), but two other cis-Golgi proteins formed small punctate structures. After BFA removal, these puncta coalesced first, and then the Golgi stacks regenerated from them in the cis-to-trans order. We suggest that these structures have a property similar to the ER-Golgi intermediate compartment and function as the scaffold of Golgi regeneration.
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