On this page
NBAS
NBAS subunit of NRZ tethering complex
NBAS is located on the short (p) arm of chromosome 2, at band 2p24.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 2 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The NBAS gene provides instructions for producing a large protein that serves as a scaffolding component of the NRZ tethering complex, a multi-subunit assembly critical for intracellular vesicle transport. This complex facilitates the movement of cargo-containing vesicles from the Golgi apparatus to the endoplasmic reticulum, a process essential for maintaining cellular protein quality control and secretory function.
Pathogenic variants in NBAS follow an autosomal recessive inheritance pattern, meaning affected individuals typically carry altered copies inherited from both parents. Clinical presentations range from isolated liver dysfunction to multisystem disorders involving bone development, growth, vision, and immune function. The gene's importance is reflected in its inclusion on multiple NHS clinical genomic panels covering hepatic, skeletal, and developmental conditions.
What the gene does
The NBAS protein functions primarily as a structural scaffold within the NRZ tethering complex, alongside its binding partners ZW10, RINT1, and USE1. This molecular assembly operates at the interface between the Golgi apparatus and the endoplasmic reticulum, where it captures vesicles returning from the Golgi and facilitates their membrane fusion with the endoplasmic reticulum.
This retrograde transport pathway serves multiple cellular functions. It retrieves proteins that have been accidentally transported forward from the endoplasmic reticulum to the Golgi, returning them to their proper location. The pathway also enables the endoplasmic reticulum to maintain its membrane composition and to receive signals from other compartments. When NBAS function is compromised, cells experience disrupted protein trafficking, accumulation of misfolded proteins, and activation of cellular stress responses. These molecular consequences appear particularly detrimental in hepatocytes and developing bone cells, though the precise tissue-specific vulnerabilities remain an active area of research.
Video: Genetics 101
Chromosome location
NBAS is located on the short arm of chromosome 2 at position 2p24.3. The gene spans a substantial genomic region encoding a large multi-exon transcript. This chromosomal region contains multiple genes, but pathogenic variants in NBAS itself account for the associated clinical phenotypes rather than broader deletions or chromosomal anomalies.
Protein structure
The NBAS protein comprises 2,371 amino acids organised into functionally distinct regions. The amino-terminal portion, spanning amino acids 1 through 1,035, mediates interaction with USE1, one of the other NRZ complex components. Within this region lie two WD repeat domains: WD 1 extends from amino acids 130 to 169, and WD 2 spans amino acids 316 to 355. These WD repeats typically form beta-propeller structures that serve as platforms for protein-protein interactions.
The carboxy-terminal region, encompassing amino acids 1,036 through 2,371, provides binding interfaces for ZW10 and RINT1, completing the multi-protein tethering assembly. This modular architecture allows NBAS to serve as a central organising scaffold, simultaneously anchoring multiple partners and coordinating the complex's function at membrane contact sites.
Key variants
Pathogenic variants in NBAS are distributed across the gene's coding sequence, with many affecting the protein's ability to maintain complex stability or interact properly with binding partners. Missense variants that alter single amino acids represent a common class of pathogenic change, often disrupting critical structural elements or interaction surfaces. Nonsense and frameshift variants that truncate the protein also occur, typically resulting in loss of essential functional domains.
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.2591dup | p.Leu864fs | Pathogenic/Likely pathogenic | ★★☆☆ | Short stature-optic atrophy-Pelger-Huët anomaly syndrome |
c.3333_3334del | p.Cys1112fs | Pathogenic | ★★☆☆ | Retinal disorder |
c.3683_3689dup | p.Leu1231fs | Pathogenic | ★★☆☆ | Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins |
c.3706C>T | p.Arg1236Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Short stature-optic atrophy-Pelger-Huët anomaly syndrome |
c.3970C>T | p.Gln1324Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.425dup | p.Tyr142Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Short stature-optic atrophy-Pelger-Huët anomaly syndrome |
c.5356C>T | p.Arg1786Ter | Pathogenic | ★★☆☆ | Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins |
c.5547del | p.Trp1850fs | Pathogenic | ★★☆☆ | Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins |
c.5883_5884dup | p.Leu1962fs | Pathogenic/Likely pathogenic | ★★☆☆ | Short stature-optic atrophy-Pelger-Huët anomaly syndrome |
c.6448_6449del | p.Asp2149_Ile2150insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Short stature-optic atrophy-Pelger-Huët anomaly syndrome |
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
Biallelic pathogenic variants in NBAS cause a spectrum of autosomal recessive disorders characterised by variable combinations of liver dysfunction, skeletal abnormalities, growth impairment, and additional systemic features. The hepatic manifestations often include recurrent episodes of acute liver failure triggered by fever or infection, with enzyme elevations and cholestasis. Some affected individuals present with bone abnormalities including short stature and skeletal dysplasia. Optic nerve involvement and immune dysfunction have also been documented in subsets of patients, reflecting the protein's broad cellular importance.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NBAS 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
NBAS appears on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical relevance across diverse diagnostic pathways. The gene holds green (high-evidence) classification on the Cholestasis panel, the Fetal anomalies panel, the Monogenic short stature panel, and the Skeletal dysplasia panel. It also appears on green-rated panels for Optic neuropathy, Osteogenesis imperfecta, and Retinal disorders. This multi-panel presence indicates that NBAS variants should be considered in differential diagnoses spanning hepatic, skeletal, growth, and ophthalmological presentations encountered in NHS clinical genetics services.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does NBAS follow?
NBAS-related conditions follow an autosomal recessive inheritance pattern. This means an individual must inherit pathogenic variants from both parents to develop the condition, whilst carriers with a single variant typically remain unaffected.
Why does NBAS dysfunction particularly affect the liver?
Hepatocytes have exceptionally high demands for protein synthesis and secretion, making them particularly vulnerable to disruptions in vesicle transport between the endoplasmic reticulum and Golgi. When NBAS function is compromised, these cells struggle to manage protein trafficking and respond poorly to additional stressors such as fever or infection.
Is NBAS testing available through the NHS?
Yes, NBAS sequencing is included in multiple NHS Genomic Medicine Service panels, including those for cholestasis, skeletal dysplasia, and short stature. Eligibility for testing depends on clinical presentation and is determined through referral to clinical genetics services.