A mutation in the UBA1 gene is a genetic alteration linked to distinct health conditions. How these conditions manifest depends on how the mutation arises and which cells in the body are affected. Scientific understanding of UBA1 mutations has grown significantly since 2020 with the identification of a new adult-onset inflammatory disorder, providing answers for patients with previously unexplained symptoms.
The UBA1 Gene and Its Cellular Function
The UBA1 gene contains instructions for making the ubiquitin-activating enzyme E1. This enzyme performs the first step in a process known as the ubiquitin-proteasome system (UPS). The UPS is the cell’s primary waste disposal and quality control mechanism, responsible for breaking down proteins that are damaged or no longer needed. This process is necessary for maintaining a healthy balance of proteins, a state called protein homeostasis.
To begin this process, the UBA1 enzyme activates a small protein called ubiquitin. This activated ubiquitin is then used to tag an unwanted protein. A chain of these tags signals a structure called the proteasome to break the targeted protein down. This system ensures that cells can clear out old proteins and function normally.
Mechanisms and Types of UBA1 Mutations
Mutations in the UBA1 gene occur in two different ways. The first is a somatic mutation, which is not inherited but acquired during a person’s lifetime. These changes happen in a single cell and are passed to all new cells derived from it, meaning the mutation is present in only a fraction of the body’s cells. Somatic UBA1 mutations are the cause of VEXAS syndrome.
The second type is a germline mutation, which is inherited from a parent and is present in every cell from birth. These mutations are responsible for X-linked infantile spinal muscular atrophy. Because the UBA1 gene is located on the X chromosome, the inheritance pattern is X-linked. This means males, who have only one X chromosome, are predominantly affected by these disorders.
VEXAS Syndrome and Its Link to UBA1
VEXAS syndrome is an inflammatory disease first described in 2020 that begins in adulthood, affecting men over 50. The name is an acronym describing its features: Vacuoles in cells, E1 enzyme (UBA1), X-linked, Autoinflammatory, and Somatic mutation. The condition is caused by somatic mutations in the UBA1 gene within hematopoietic stem cells, the cells in bone marrow that produce all blood cells.
The most common mutation is a missense mutation at the methionine-41 (Met41) position, leading to a dysfunctional enzyme. This impairment disrupts the cell’s ability to clear unwanted proteins, causing cellular stress and overactivating inflammatory pathways in myeloid immune cells. The result is chronic, systemic inflammation.
Clinical features are widespread and include recurrent fevers, painful skin rashes, and inflammation of cartilage in the ears and nose. Patients may also develop inflamed blood vessels, lung problems, and joint pain. The syndrome impacts the blood, causing macrocytic anemia, low platelet counts, and an increased risk of blood cancers like myelodysplastic syndrome (MDS).
UBA1 Mutations in X-linked Infantile Spinal Muscular Atrophy
Inherited germline mutations in the UBA1 gene cause a different and very rare disorder known as X-linked infantile spinal muscular atrophy (SMAX2). This neurological condition presents at birth or in early infancy with severe muscle weakness and a lack of reflexes. SMAX2 results from the death of motor neurons in the spinal cord.
Infants with SMAX2 often have joint contractures from birth, a weak cry, and are described as “floppy.” The muscle weakness affects the entire body, including the chest muscles required for breathing. This often leads to respiratory failure and death in early childhood. These mutations cause a significant reduction in the UBA1 enzyme’s function, which is devastating to motor neurons.
Diagnostic Approaches for UBA1 Mutations
Identifying UBA1 mutations requires specific genetic testing, and the method depends on the suspected condition. For both VEXAS syndrome and SMAX2, gene sequencing techniques like Sanger sequencing or next-generation sequencing (NGS) are used to read the DNA code of the UBA1 gene.
Diagnosing VEXAS syndrome is complex because the somatic mutation is only in a subset of cells. A standard blood test might miss the mutation if it is at a low frequency. Testing DNA from peripheral blood myeloid cells, a bone marrow sample, or affected skin tissue is often necessary for an accurate diagnosis. UBA1 testing may be considered for older men who present with unexplained inflammatory symptoms combined with blood abnormalities like macrocytic anemia.
For SMAX2, the germline mutation can be detected from a standard blood sample since it is present in all cells. Diagnosis is considered in male infants with severe muscle weakness and joint contractures. Genetic testing confirms the diagnosis and distinguishes it from other forms of spinal muscular atrophy caused by different gene mutations.