EPG5 gene (EPG5 is the acronym for Ectopic P-granules autophagy protein 5 homolog) is located on chromosome 18q12.3-q21.1 and encodes for a protein that plays a key role in the autophagy pathway.
Autophagy is a highly conserved lysosomal degradation pathway with fundamental roles in cellular homeostasis, embryonic development, and muscle remodeling. Orthologs of EPG5 can be detected in mammals, fish, flies, and worms.
The encoded protein contains 1,457 amino acids and can be detected in all adult and fetal tissues, with the highest expression in the adult ovary and whole brain and in most specific adult brain regions examined. EPG5 expression was lower in the fetal brain than in the adult brain.
Mutations in the EPG5 gene are associated with Vici syndrome.
Vici syndrome is a rare congenital multisystem disorder characterized by profound psychomotor retardation, agenesis of the corpus callosum, pigmentary abnormalities, cataracts, progressive cardiomyopathy, myopathy, and variable immunodeficiency.
In 16 patients from 13 unrelated families with Vici syndrome, Cullup et al (2013) identified homozygous or compound heterozygous mutations in the EPG5 gene. All mutations were truncating or splice site mutations, except for 2 that were missense mutations. The first mutations were identified by exome sequencing of 4 patients from 3 families, and the remaining mutations were identified by screening the EPG5 gene in 12 additional families. Two families with the disorder did not have EPG5 mutations, suggesting genetic heterogeneity.
Molecular studies of Vici syndrome suggested that Vici syndrome results from defective autophagy. The skeletal muscle tissue of the patients showed disproportion of fiber types with type 1 atrophy and numerous vacuolar-like areas. Immunofluorescence studies of skeletal muscle from 2 patients showed upregulation of the sarcomere-associated autophagy proteins SQSTM1 (p62) (601530) and NBR1 (166945) with numerous puncta, indicating accumulation of autophagosomes in EPG5-deficient cells. Treatment of patient and control cells with autophagy inducers and inhibitors indicated that patient cells had a severe deficit in autophagosomal clearance and impaired fusion to lysosomes. The findings were consistent with the histopathological features of defective autophagy, including storage of abnormal material and secondary mitochondrial abnormalities in skeletal muscle and multisystem defects in the heart, immune system, skin pigmentation, and central nervous system, suggesting defective autophagy in various tissues.
In a male infant born to consanguineous Iranian parents with Vici syndrome, Ehmke et al. (2014) identified a homozygous truncating mutation in the penultimate exon (exon 43) of the EPG5 gene (R2483X; 615068.0006).
Maillard et al. (2017) identified compound heterozygosity for a missense (G1336E; 615068.0007) and a frameshift mutation (615068.0008) in the EPG5 gene by whole-exome sequencing in a 2-year-old girl from unrelated parents with Vici syndrome. One of the mutations was detectable in each parent.