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GORAB
golgin, RAB6 interacting
GORAB is located on the long (q) arm of chromosome 1, at band 1q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
GORAB (golgin, RAB6 interacting) is located on chromosome 1 and encodes a 369 amino acid protein that resides in the golgi apparatus. The golgi acts as the cell's sorting and packaging centre, modifying proteins and directing them to their proper destinations. GORAB appears to play a specialised role in maintaining golgi structure and function, particularly in cells that produce the extracellular matrix components required for healthy bone and skin.
Pathogenic variants in GORAB follow an autosomal recessive inheritance pattern, meaning two altered copies are required to cause disease. The gene is included in multiple NHS Genomic Medicine Service panels related to skeletal dysplasia and connective tissue disorders, reflecting its clinical importance in diagnosing rare developmental conditions affecting the musculoskeletal system.
What the gene does
The GORAB protein functions as a golgin, a family of proteins that maintain the structure and organisation of the golgi apparatus. These proteins act as molecular tethers, anchoring transport vesicles and coordinating the movement of cargo between different cellular compartments. GORAB specifically interacts with RAB6, a small regulatory protein that controls vesicle trafficking, and with RCHY1, a protein involved in cellular signalling pathways.
Within cells that produce extracellular matrix, GORAB appears particularly important for the proper processing and secretion of structural proteins. The extracellular matrix provides scaffolding and support for tissues throughout the body, and its composition must be precisely controlled during skeletal development. When GORAB function is compromised, cells cannot properly package and export matrix components, leading to defects in bone mineralisation and connective tissue integrity. The protein's role in golgi organisation may also affect how cells respond to stress and maintain their internal architecture during periods of rapid growth.
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Chromosome location
GORAB is located on the long arm of chromosome 1 at position 24.2 (1q24.2). This chromosomal region contains numerous genes involved in skeletal development and connective tissue formation. The genomic structure and total number of exons for GORAB have not been extensively characterised in publicly available databases, though the gene produces a transcript encoding a 369 amino acid protein.
Protein structure
The GORAB protein contains several structural features that reflect its function in the golgi apparatus. The N-terminal portion (amino acids 1-128) is disordered, lacking fixed three-dimensional structure and likely providing flexibility for protein interactions. A prominent coiled coil region spans amino acids 145-297, a common structural motif in golgins that enables protein-protein interactions and membrane anchoring. The C-terminal region (amino acids 188-369) is necessary for interaction with RCHY1, a key binding partner. The final segment (amino acids 334-369) is also disordered, potentially allowing dynamic conformational changes during vesicle tethering and cargo sorting.
Key variants
Pathogenic variants in GORAB are associated with loss of protein function, typically through premature termination, frameshift changes, or alterations that destabilise the protein structure. Because the condition follows autosomal recessive inheritance, affected individuals carry pathogenic variants on both gene copies. Carrier status, with one altered copy, does not typically cause health problems but can be identified through genetic screening.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.103C>T | p.Arg35Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.118C>T | p.Arg40Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Geroderma osteodysplastica |
c.190C>T | p.Gln64Ter | Pathogenic | ★★☆☆ | Geroderma osteodysplastica |
c.257del | p.Pro86fs | Pathogenic/Likely pathogenic | ★★☆☆ | Geroderma osteodysplastica |
c.408_409del | p.Lys137fs | Pathogenic/Likely pathogenic | ★★☆☆ | Geroderma osteodysplastica |
c.420-2A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.784C>T | p.Arg262Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Geroderma osteodysplastica |
GRCh37/hg19 1q24.2(chr1:170471185-170529811)x1 | - | Pathogenic | ★☆☆☆ | not specified |
c.679_680insATCTTTATACACATCCTTACAGGAAGCGGTA | p.Ala227fs | Pathogenic | ★☆☆☆ | not provided |
c.679del | p.Ala227fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in GORAB cause geroderma osteodysplastica, a rare autosomal recessive disorder characterised by premature ageing of the skin (geroderma) and skeletal abnormalities (osteodysplastica). Affected individuals typically present in childhood with loose, wrinkled skin and reduced bone density, leading to increased fracture risk. The condition reflects the protein's essential role in maintaining both connective tissue and skeletal integrity during development and growth.
Inheritance pattern
Conditions caused by pathogenic GORAB variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
GORAB is included on multiple NHS Genomic Medicine Service gene panels with green (high evidence) classification. These include the skeletal dysplasia panel (R104), osteogenesis imperfecta panel (R102), and Ehlers-Danlos syndrome panel (R101), reflecting its established role in connective tissue and bone disorders. The gene also appears on panels for foetal anomalies (R21), congenital disorders of glycosylation, and likely inborn errors of metabolism (R98), indicating its relevance across prenatal and paediatric diagnostic pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is GORAB inherited?
GORAB-related conditions follow autosomal recessive inheritance. This means a person must inherit two altered copies of the gene, one from each parent, to develop the condition. Parents who each carry one altered copy typically have no symptoms but have a 25% chance with each pregnancy of having an affected child.
What does it mean if I am a carrier of a GORAB variant?
Carriers have one working copy and one altered copy of GORAB. Carriers typically do not experience health problems related to the gene. However, if both parents are carriers, there is a risk of having a child with geroderma osteodysplastica.
Why is GORAB on multiple NHS panels?
GORAB appears on several panels because the associated condition affects multiple systems - skeletal development, connective tissue, and skin. This ensures the gene is considered when patients present with overlapping features such as bone fragility, joint laxity, or premature skin ageing, supporting accurate diagnosis across different clinical pathways.