Dissecting the function of GORAB, the protein mutated in Geroderma osteodysplastica

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences


Skin, bone, cartilage and connective tissues in our body are clearly important, providing a range of functions that are essential for life. The components of all of these tissues are made inside special types of cells in our body, which then release, or secrete, them outside the cell, upon which the individual components assemble to form complex networks that ultimately generate the physical structure of the particular tissue. The secreted components are typically large proteins that undergo extensive modifications prior to and after their secretion from the cell. The secreted proteins are synthesized in a particular compartment inside the cell called the endoplasmic reticulum, where many undergo extensive modification, commonly involving the addition of linked chains of sugars in a process termed glycosylation. Proteins are then transported in small spherical packets to another compartment called the Golgi apparatus, where further glycosylation and processing of the added sugar chains occurs. The modified proteins are then packaged at the Golgi apparatus into different vesicles for delivery to the cell surface and release from the cell.

Many human diseases affect the formation or maintenance of the skin and bones, and moreover, it is well known that both tissues degenerate as people get older. A rare genetic disorder called Geroderma osteodysplastica causes loose, wrinkly skin and osteoporosis, symptoms similar to those seen in ageing. The cause of GO is mutation of a gene that encodes for a Golgi apparatus protein called GORAB. The function of GORAB is not known, and consequently we do not understand how the symptoms of GO are brought about. We have obtained preliminary evidence that GORAB is important for vesicle transport at the Golgi complex and for the correct processing of sugar chains on cargo proteins transiting through this compartment. Hence, we propose that GO is caused by defective modification of proteins that make up the skin and bone, leading to the pathological effects that are observed in these tissues. The work described here aims to determine the precise function of GORAB in Golgi vesicle transport, and then to determine how the loss of GORAB affects modification of secreted proteins, focusing on those that make up the skin. The work will not only be important for determining the mechanisms of GO, but have more widespread significance for our understanding of cargo modification more generally, which is of fundamental importance to all cells. Moreover, the results will inform us of how the skin is assembled, and how the skin changes both in disease but also likely during the normal ageing process. Finally, the work also has relevance to our understanding of processes such as tissue regeneration and wound repair.

Technical Summary

Geroderma osteodysplastica (GO) can be classified a progeroid disorder, with characteristic symptoms of loose, wrinkly skin (cutis laxa) and osteoporosis. GO is caused by mutation of GORAB, also called Scyl1BP1, a coiled-coil protein localised to the Golgi apparatus. The cellular function of GORAB is not known, and we do not know how its loss leads to the pathological changes observed in GO patients. In preliminary studies we have found novel interactions between GORAB and components of the COPI machinery that mediates intra-Golgi trafficking. We have also observed changes in protein glycosylation in GO patient cells, consistent with altered intra-Golgi trafficking of glycosylation enzymes. We therefore propose that GORAB functions in intra-Golgi trafficking of glycosylation enzymes, and that GO is a genetic disorder whose symptoms are attributable to defective glycosylation of extracellular matrix proteins comprising the skin and bone. We aim to investigate these hypotheses using a combination of biochemical and cell biological approaches using both cultured cell lines, including GO patients' dermal fibroblasts, and patient-derived skin biopsies. Together the findings will reveal the mechanistic basis for GO, and also inform us more generally of how COPI mediated trafficking and protein glycosylation are controlled. The work also has relevance to our understanding of ageing and tissue maintenance and repair, which are dependent upon proper generation and maintenance of the extracellular matrix.

Planned Impact

Wherever possible we will try to maximise the impact of our research. We will adopt several strategies to achieve this, as indicated below.

Beneficiaries of the research
We envisage that findings of our current study will be of interest to the public at large given the clinical importance of the processes we will investigate in the proposal. We will communicate our findings to the public via the open access University website and through the Faculty of Life Science (FLS) and Faculty of Medical and Human Sciences (FMHS) research brochures. We will also notify the dedicated Faculty press officers of our findings at around the point of publication in academic journals. The press officer will then contact local and national news agencies, and prepare press releases that these agencies can use. We will also contact appropriate stakeholders including cutis laxa patients and their families and associated health care professionals. In this regard Dr Tassabehji has already interacted with the patient group CUTIS LAXA INTERNATIONALE and the GeneSkin and Orphanet organizations, and remains in close contact with them. The Lowe and Tassabehji laboratories have participated in several public engagement initiatives and we plan for this to continue. The labs have hosted several A-level students at different times as part of the Nuffield bursary scheme. The FLS and FMHS continue to participate in the Nuffield scheme and we envisage hosting another 1-2 A-level students should the current application be successful. Members of the Lowe lab have participated in several public engagement exercises involving visiting schoolchildren, hosted at the Manchester Museum with whom the University has close links. Members of the Lowe and Tassabehji labs will continue to participate in these exercises in the future.

Exploitation and application
The work outlined in the proposal is basic research. Thus it is not trivial to realize the short and long term benefit of the work in terms of direct commercial or clinical exploitation. However, the scientific data obtained will increase the knowledge of UK and international scientists in the academic, clinical and commercial sectors. This contribution to knowledge will lead to improved understanding of human disease mechanisms that in turn will aid the design of better diagnosis and treatments for patients. This is particularly relevant to Geroderma osteodysplastica (GO) and other cutis laxa syndromes, but more broadly to other disorders affecting the skin and bones (the two major affected tissues in GO). Moreover, because GO is a progeroid disorder, our work is highly relevant to the understanding of ageing. Indeed we envisage that the findings obtained in our study can used in the short term to better understand and detect changes that occur in ageing skin. These improvements then can then be translated in the longer term to improved 'therapy' to ameliorate the ageing process. Moreover, 'anti-ageing' cosmetic treatments constitute a multi-million pound industry, and any advancement in understanding how skin ageing occurs is likely to have translatable benefit in this commercially important sector. Finally, because our work will improve understanding of extracellular matrix assembly and maintenance in skin, it may also have applications in the areas of regenerative medicine and wound healing.

The technical and intellectual knowledge acquired by the post-doctoral researchers during the course of the proposed work will equip these people to pursue a career in science or science-related discipline. The researchers will also learn transferable skills that will increase their employability. Such highly trained individuals will contribute to the UK knowledge and skill base and ultimately the UK economy.
Description A new role for intermediate filaments in the secretory pathway
Amount £481,165 (GBP)
Funding ID BB/T000945/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 08/2022
Description Coordination of membrane traffic in the early secretory pathway
Amount £463,442 (GBP)
Funding ID BB/S014799/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2019 
End 06/2022
Title Generation of antibodies and cDNA constructs for GORAB and interacting proteins 
Description Generated 2 polyclonal antibodies to the Golgi protein GORAB, which is mutated in the human disorder gerodermia osteodysplastica. We also generated antibodies to the binding partner called Scyl1, whose mutation causes CALFAN syndrome in humans. Finally, we generated numerous cDNA constructs to these proteins. 
Type Of Material Antibody 
Year Produced 2019 
Provided To Others? Yes  
Impact Cannot say. It is too early. 
Description Collaboration with Ekkehart Lausch, University of Freiburg University Hospital 
Organisation University Medical Center Freiburg
Country Germany 
Sector Hospitals 
PI Contribution We have contributed cell biology expertise to two collaborative research projects. One is on the identification of a new pathological mechanism for a disease known as Achondrogenesis Type 1A. The second is on the identification of a new molecular cause for a disease known as Odontochondrodysplasia. In both cases we have performed imaging and functional experiments.
Collaborator Contribution They have identified patients and performed clinical studies on them.They have also performed some molecular analyses.
Impact We have 2 papers currently in preparation.
Start Year 2016
Description Collaboration with Uwe Kornak, Max Planck Institute for Medical Genetics 
Organisation Max Planck Society
Country Germany 
Sector Charity/Non Profit 
PI Contribution We have contributed cell biology expertise to a project to understand the disease mechanisms of Geroderma Osteodysplastica.
Collaborator Contribution They have generated a mouse model for Geroderma Osteodysplastica to study the pathophysiology of the disorder.
Impact We have one publication under review currently, and another that is about to be submitted.
Start Year 2016