Alternative titles; symbols
HGNC Approved Gene Symbol: EPG5
SNOMEDCT: 719824001;
Cytogenetic location: 18q12.3-q21.1 Genomic coordinates (GRCh38) : 18:45,800,581-45,967,329 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.3-q21.1 | Vici syndrome | 242840 | Autosomal recessive | 3 |
EPG5 is the human homolog of the C. elegans epg5 gene, which encodes a protein with 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 (summary by Cullup et al., 2013).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned EPG5, which they designated KIAA1632. The deduced protein contains 1,457 amino acids. RT-PCR ELISA detected robust EPG5 expression in all adult and fetal tissues examined, with highest expression in adult ovary and whole brain and in most specific adult brain regions examined. EPG5 expression was lower in fetal brain than in adult brain.
Halama et al. (2007) determined that the full-length EPG5 protein contains 2,579 amino acids. They identified orthologs of EPG5 in mammals, fish, flies, and worms.
Halama et al. (2007) determined that the EPG5 gene contains 44 exons.
By PCR of a human-rodent hybrid panel, Nagase et al. (2000) mapped the EPG5 gene to chromosome 18. Halama et al. (2007) mapped the EPG5 gene to chromosome 18q12.3-q21.1 by genomic sequence analysis.
In 16 patients from 13 unrelated families with Vici syndrome (VICIS; 242840), Cullup et al. (2013) identified homozygous or compound heterozygous mutations in the EPG5 gene (see, e.g., 615068.0001-615068.0005). All of the 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 rest of the mutations were identified by screening of the EPG5 gene in 12 additional families. Two families with the disorder did not have EPG5 mutations, suggesting genetic heterogeneity. Vici syndrome is a rare congenital multisystem disorder characterized by profound psychomotor retardation, agenesis of the corpus callosum, pigmentary defects, cataracts, progressive cardiomyopathy, myopathy, and variable immunodeficiency. The molecular studies suggested that Vici syndrome results from defective autophagy. Patient skeletal muscle tissue showed fiber-type disproportion with type 1 atrophy and numerous vacuole-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 suggested that patient cells had a severe deficit in autophagosomal clearance and impaired fusion to lysosomes. The findings were consistent with histopathologic features of defective autophagy, including storage of abnormal material and secondary mitochondrial abnormalities in skeletal muscle, as well as multisystem defects in the heart, immune system, skin pigmentation, and central nervous system, implicating defective autophagy in various tissues.
In a male infant, born of 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).
By whole-exome sequencing in a 2-year-old girl, born of unrelated parents, with Vici syndrome, Maillard et al. (2017) identified compound heterozygosity for a missense (G1336E; 615068.0007) and a frameshift (615068.0008) mutation in the EPG5 gene. Each parent carried one of the mutations.
Zhao et al. (2013) found that Epg5-null mice developed progressive neurologic symptoms with hind limb paralysis around 4 months of age, resulting in death at 10 to 12 months. Autophagy flux was impaired, resulting in the accumulation of SQSTM1 aggregates in only certain neuronal populations in the central nervous system, including anterior horn cells of the spinal cord but not Purkinje cells in the cerebellum. Mutant mice also had severe muscle atrophy and muscle denervation, reminiscent of amyotrophic lateral sclerosis (ALS; 105400). The mice showed only some features of Vici syndrome, including thin corpus callosum and muscle atrophy, but other core features, such as growth retardation, dysmorphic facial features, cataract, hypopigmentation, and immunodeficiency, were not present.
In 2 sibs with Vici syndrome (VICIS; 242840), originally reported by Dionisi Vici et al. (1988), Cullup et al. (2013) identified compound heterozygosity for 2 mutations in the EPG5 gene: a 4588C-T transition, resulting in a gln1530-to-ter (Q1530X) substitution, and a 1-bp duplication (5704dupT), resulting in a frameshift and premature termination (Tyr1902LeufsTer2; 615068.0002). Both patients died by age 3 years.
For discussion of the 1-bp duplication in the EPG5 gene (5704dupT) that was found in 2 sibs with Vici syndrome (VICIS; 242840) by Cullup et al. (2013), see 615068.0001.
In 2 sibs, born of consanguineous parents, with Vici syndrome (VICIS; 242840), Cullup et al. (2013) identified a homozygous 3481C-T transition in the EPG5 gene, resulting in an arg1161-to-ter (R1161X) substitution.
In 2 sibs, born of consanguineous parents, with Vici syndrome (VICIS; 242840), Cullup et al. (2013) identified compound heterozygosity for 2 nonsense mutations in the EPG5 gene: a 2575G-T transversion resulting in a glu859-to-ter (E859X) substitution, and a 6232C-T transition resulting in an arg2078-to-ter (R2078X; 615068.0005) substitution. Both patients died at age 8 years.
For discussion of the arg2078-to-ter (R2078X) mutation in the EPG5 gene that was found in compound heterozygous state in 2 sibs with Vici syndrome (VICIS; 242840) by Cullup et al. (2013), see 615068.0004.
In a male infant, born of consanguineous Iranian parents, with Vici syndrome (VICIS; 242840), Ehmke et al. (2014) identified a homozygous c.7447C-T transition (c.7447C-T, NM_020964.2) in the penultimate exon (exon 43) of the EPG5 gene, resulting in an arg2483-to-ter (R2483X) substitution. The mutation was predicted to result in nonsense-mediated mRNA decay, but functional studies and studies on patient cells were not performed. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
By whole-exome sequencing in a 2-year-old girl, born of unrelated parents, with Vici syndrome (VICIS; 242840), Maillard et al. (2017) identified compound heterozygosity for mutations in the EPG5 gene: a c.4007G-A transition (c.4007G-A, NM_020964.2), resulting in a gly1336-to-glu (G1336E) substitution, and a 1-bp insertion (c.2352_2353insG), resulting in a frameshift and premature termination (Ala785GlyfsTer20; 615068.0008). The missense mutation was inherited from the mother and the frameshift mutation from the father. Neither mutation was found in the dbSNP, Exome Sequencing Project, or ExAC databases.
For discussion of the 1-bp insertion (c.2352_2353insG, NM_020964.2) in the EPG5 gene, resulting in a frameshift and a premature stop codon (Ala785GlyfsTer20), that was found in a girl with Vici syndrome (VICIS; 242840) by Maillard et al. (2017), see 615068.0007.
Cullup, T., Kho, A. L., Dionisi-Vici, C., Brandmeier, B., Smith, F., Urry, Z., Simpson, M. A., Yau, S., Bertini, E., McClelland, V., Al-Owain, M., Koelker, S., and 25 others. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature Genet. 45: 83-87, 2013. [PubMed: 23222957] [Full Text: https://doi.org/10.1038/ng.2497]
Dionisi Vici, C., Sabetta, G., Gambarara, M., Vigevano, F., Bertini, E., Boldrini, R., Parisi, S. G., Quinti, I., Aiuti, F., Fiorilli, M. Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am. J. Med. Genet. 29: 1-8, 1988. [PubMed: 3344762] [Full Text: https://doi.org/10.1002/ajmg.1320290102]
Ehmke, N., Parvaneh, N., Krawitz, P., Ashrafi, M.-R., Karimi, P., Mehdizadeh, M., Kruger, U., Hecht, J., Mundlos, S., Robinson, P. N. First description of a patient with Vici syndrome due to a mutation affecting the penultimate exon of EPG5 and review of the literature. Am. J. Med. Genet. 164A: 3170-3175, 2014. [PubMed: 25331754] [Full Text: https://doi.org/10.1002/ajmg.a.36772]
Halama, N., Grauling-Halama, S. A., Beder, A., Jager, D. Comparative integromics on the breast cancer-associated gene KIAA1632: clues to cancer antigen domain. Int. J. Oncology 31: 205-210, 2007.
Maillard, C., Cavallin, M., Piquand, K., Philbert, M., Bault, J. P., Millischer, A. E., Moshous, D., Rio, M., Gitiaux, C., Boddaert, N., Masson, C., Thomas, S., Bahi-Buisson, N. Prenatal and postnatal presentations of corpus callosum agenesis with polymicrogyria caused by EGP5 (sic) mutation. Am. J. Med. Genet. 173A: 706-711, 2017. [PubMed: 28168853] [Full Text: https://doi.org/10.1002/ajmg.a.38061]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Zhao, Y. G., Zhao, H., Sun, H., Zhang, H. Role of Epg5 in selective neurodegeneration and Vici syndrome. Autophagy 9: 1258-1262, 2013. [PubMed: 23674064] [Full Text: https://doi.org/10.4161/auto.24856]