The SERAC1 gene encodes for a protein necessary for phosphatidylglycerol remodeling. phosphatidylglycerol remodeling is a process of altering or remodeling a particular phospholipid called phosphatidylglycerol. Phosphatidylglycerol helps make cardiolipin, an important ingredient that surrounds the Inner mitochondrial membrane. Cardiolipin is responsible for converting energy acquired from food to a cell-usable form and required for proper mitochondrial function. Because of cardiolipin, the remodeling process of phosphatidylglycerol is essential for mitochondrial function and intracellular cholesterol trafficking. Additionally, SERAC1 is involved in the movement of cholesterol, which are fatty, waxy substances within cells. Cholesterol is a component of cell structure, and produces hormones and digestive acids. The protein may also be involved in the transacylation-acylation reaction to produce phosphatidylglycerol-36:1 and bisphosphate biosynthetic pathway.
Clinical Significance
Mutations in the SERAC1 gene have been associated to impairment of both mitochondrial function and intracellular cholesterol trafficking. Such mutations have been majorly associated withand Leigh syndrome and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, known as MEGDEL syndrome.
MEGDEL syndrome
SERAC1 mutations have been heavily associated with MGDEL syndrome. MGDEL syndrome is an autosomal recessive disorder characterized by childhood onset of delayed psychomotor development or psychomotor regression, sensorineural deafness, spasticity or dystonia and increased excretion of 3-methylglutaconic acid. Brain imaging shows cerebral and cerebellaratrophy as well as lesions in the basal ganglia reminiscent of Leigh syndrome. Laboratory studies show increased serumlactate and alanine, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, abnormal phosphatidylglycerol and cardiolipin profiles in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. The SERAC1 gene mutations that cause this condition reduce the amount of SERAC1 protein that is produced or lead to production of a protein with little or no function. As a result, phosphatidylglycerol remodeling is impaired, which likely alters the composition of cardiolipin. Researchers speculate that the abnormal cardiolipin affects mitochondrial function, reducing cellular energy production and leading to the neurological and hearing problems characteristic of MEGDEL syndrome. It is unclear how SERAC1 gene mutations lead to abnormal release of 3-methylglutaconic acid in the urine. A c.202C>T mutation in this gene has been found in a patient suffering from 3-methylglutaconic aciduria, and related symptoms. Two patients with Homozygous G>C transversions in the SERAC1 gene have been found to show symptoms of MEGDEL syndrome with deafness, encephalopathy, and Leigh-like syndrome. Another patient with a homozygous 4 base pair deletion showed symptoms of recurrent infections, failure to thrive, mental retardation, spasticity and extrapyramidal symptoms.
