Sialin is a transporter protein that moves specific materials between locations inside the cell. This function is part of how cells manage waste, recycle components, and maintain operational stability. When this transport is disrupted, cellular processes can fail, leading to significant health consequences.
The Cellular Role of Sialin
Cells contain compartments called lysosomes, which act as the recycling and waste disposal system. Lysosomes use enzymes to break down complex molecules into simpler components. The sialin protein is located on the membrane of the lysosome, where it functions as a transporter for its primary cargo, a sugar molecule called free sialic acid.
After larger molecules are broken down, sialin moves the resulting free sialic acid out of the lysosome and into the cell’s cytoplasm. This allows the sialic acid to be reused by the cell for other functions, like cell-to-cell communication. The instructions for building the sialin protein are encoded in the SLC17A5 gene.
Sialin operates as a proton-coupled transporter, using energy from a proton gradient to move sialic acid across the membrane. This mechanism is a symport system, and it moves a proton along with each sialic acid molecule to ensure efficient transport.
Sialin Dysfunction and Lysosomal Storage
Mutations in the SLC17A5 gene can disrupt the production of a functional sialin protein. Some mutations prevent the protein from being made, while others result in a malformed protein that is non-functional. In some cases, the sialin protein is produced but fails to travel to the lysosomal membrane.
When sialin is absent or non-functional, free sialic acid cannot be transported out of the lysosome and accumulates inside. As the concentration of sialic acid increases, the lysosome swells. This swelling interferes with its function and impacts the overall health of the cell.
The accumulation of a substance within the lysosome is the defining characteristic of lysosomal storage disorders. The conditions caused by faulty sialin are categorized as free sialic acid storage disorders (FSASDs). These disorders are inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated SLC17A5 gene from both parents to be affected.
Associated Medical Conditions
The malfunction of the sialin protein causes a spectrum of conditions differentiated by severity. The two main disorders are Salla disease (SD) and infantile free sialic acid storage disease (ISSD). Salla disease is the mildest form, while ISSD is the most severe.
Salla disease, named after a region in Finland with a common founder mutation, is the less severe form. Children with Salla disease appear healthy at birth, with symptoms emerging within the first year. Early signs include low muscle tone (hypotonia) and clumsiness, progressing to balance issues (ataxia) and involuntary movements (athetosis). Intellectual development is delayed, but progression is slow, and many individuals live into adulthood with significant disabilities.
Infantile free sialic acid storage disease (ISSD) is the most severe form, with symptoms presenting at or shortly after birth. In some cases, a dangerous accumulation of fluid known as hydrops fetalis can occur before birth. Infants with ISSD exhibit a range of symptoms, including:
- Severe developmental delays
- Weak muscle tone and failure to grow at a normal rate
- Distinct facial features
- Enlarged organs like the liver and spleen (hepatosplenomegaly)
- Seizures
The lifespan for individuals with ISSD is shortened to early childhood.
Diagnosis and Management
Diagnosing a free sialic acid storage disorder begins with biochemical tests to measure the amount of free sialic acid in a patient’s urine or cultured skin cells (fibroblasts). Elevated levels of sialic acid indicate a transport problem. For instance, in Salla disease, urinary excretion of free sialic acid may be increased tenfold, while in ISSD it can be elevated by as much as 100-fold.
A definitive diagnosis is achieved through genetic testing. Sequencing the SLC17A5 gene allows specialists to identify the specific mutations responsible for the faulty sialin protein. Antenatal diagnosis is also possible by measuring sialic acid in fetal cells or through genetic analysis.
There is currently no cure for these disorders, so treatment focuses on managing symptoms and providing supportive care. A multidisciplinary team provides physical therapy for motor difficulties, occupational therapy for daily activities, and speech therapy for communication. Medications are also prescribed to control symptoms like seizures.