Alternative titles; symbols
HGNC Approved Gene Symbol: EDEM3
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38) : 1:184,690,237-184,754,858 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.3 | Congenital disorder of glycosylation, type IIv | 619493 | Autosomal recessive | 3 |
Quality control in the endoplasmic reticulum (ER) ensures that only properly folded proteins are retained in the cell through recognition and degradation of misfolded or unassembled proteins. EDEM3 belongs to a group of proteins that accelerate degradation of misfolded glycoproteins in the ER (Hirao et al., 2006).
By exon trapping, cDNA library screening, and shotgun sample sequencing, Sood et al. (2001) identified EDEM3, which they called E16, within a prostate cancer susceptibility region on chromosome 1 (HPC1; 601518). The deduced protein contains more than 906 amino acids. Northern blot analysis detected a 7.5-kb transcript in all tissues examined.
Hirao et al. (2006) cloned mouse Edem3. The deduced 931-amino acid protein shares 91% identity with the human ortholog reported by Sood et al. (2001). Mouse Edem3 has the signature motifs of class I alpha-mannosidases in its N-terminal domain, a protease-associated motif in its C-terminal region, and several N-glycosylation sites. Northern blot analysis detected Edem3 expression in all mouse tissues examined, with highest levels in liver, heart, and kidney. Immunofluorescence localization showed Edem3 colocalized with ER resident proteins.
Sood et al. (2001) determined that the EDEM3 gene contains 20 exons.
By genomic sequence analysis, Sood et al. (2001) mapped the EDEM3 gene to chromosome 1q25.
Hirao et al. (2006) showed that mouse Edem3 accelerated ER-associated degradation of a misfolded alpha-1-antitrypsin (AAT, or PI; 107400) variant and TCR-alpha (TCRA; see 186880) in transfected human embryonic kidney cells. Overexpression of Edem3 stimulated mannose trimming from total glycoproteins and from misfolded AAT. Overexpression of an inactive Edem3 mutant abolished the stimulation of mannose trimming and decreased the stimulation of ER-associated protein degradation.
In 12 patients from 7 families with congenital disorder of glycosylation type 2v (CDG2V; 619493), Polla et al. (2021) identified biallelic mutations in the EDEM3 gene (610214.0001-610214.0009). The mutations were identified by whole-exome sequencing. Seven patients from 4 families had homozygous mutations, and 5 patients from 3 families had compound heterozygous mutations. All of the mutations were predicted to be protein-truncating, with the exception of compound heterozygous mutations in 1 patient (family 7). Analysis of the N-glycan profile of total plasma glycoproteins from all affected individuals showed decreased levels of M3-M7 glycan species with normal M8 and M9 species (or sometimes mildly increased M9 species) compared to controls. The M3:M4 ratio was reduced in all 12 affected patients tested, consistent with a possible role of EDEM3 in trimming M5 to shorter polymannose glycans.
Polla et al. (2021) analyzed N-glycan profiles in Edem3 knockout mice. Plasma from the knockout mice showed decreased ratios of M5:M9, M6:M9, and M7:M9 glycan species compared to controls. Plasma proteins also had significantly increased abundance of M8 and M9 glycan species. N-glycan profiles of brain lysate from knockout mice showed increased high-mannose M8 and M9 N-glycan species and decreased ratios of M5:M9 and M6:M9 species. Polla et al. (2021) concluded that these profiles were consistent with the known role of EDEM3 in trimming M8B.
In 5 Portuguese Romani patients from consanguineous families segregating congenital disorder of glycosylation type 2v (CDG2V; 619493), including 3 sibs from family 1 and 2 sibs from family 2, Polla et al. (2021) identified homozygosity for a 1-bp deletion (c.1859del, NM_025191.3) in the EDEM3 gene, predicted to result in a frameshift and premature termination (Ile620ThrfsTer7). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Comparison of the exome data from 2 affected individuals from family 1 and 1 affected individual from family 2 indicated that all 3 shared a region of homozygosity of 3.16 Mb surrounding EDEM3. In 96 control individuals in the Romani population in Portugal who were screened for the presence of the c.1859del mutation, 1 heterozygous allele was detected. EDEM3 mRNA levels were significantly decreased in lymphoblastoid cell lines from the 3 sibs in family 1, which was rescued by inhibition of nonsense mediated decay. EDEM3 mRNA levels were reduced and protein levels were absent in fibroblasts from a patient from family 1. Pulse-chase analysis of protein glycosylation in fibroblasts from the patient in family 1 was consistent with deficient EDEM3 function.
In 3 sibs (family 3) with congenital disorder of glycosylation type 2v (CDG2V; 619493), Polla et al. (2021) identified compound heterozygosity for 2 mutations in the EDEM3 gene: a 1-bp duplication (c.2001dupA, NM_025191.3), resulting in a frameshift and premature termination (Ala668SerfsTer9), and a 1-bp deletion (c.1369delA; 610214.0003), resulting in a frameshift and premature termination (Arg457GlufsTer28). The mutations were identified by trio exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. EDEM3 mRNA levels were reduced, and protein levels were absent in fibroblasts from one of the sibs. Pulse-chase analysis of protein glycosylation in fibroblasts from this sib was consistent with deficient EDEM3 function.
For discussion of the 1-bp deletion (c.1369delA, NM_025191.3) in the EDEM3 gene, resulting in a frameshift and premature termination (Arg457GlufsTer28), that was identified in compound heterozygous state in 3 sibs with congenital disorder of glycosylation type 2v (CDG2V; 619493) by Polla et al. (2021), see 610214.0002.
In a patient (family 4) with congenital disorder of glycosylation type 2v (CDG2V; 619493), Polla et al. (2021) identified homozygosity for a c.940A-T transversion (c.940A-T, NM_025191.3) in the EDEM3 gene, resulting in an arg314-to-ter (R314X) substitution. The mutation was found by whole-exome sequencing, and the patient was shown to have maternal uniparental disomy of chromosome 1. Functional studies were not performed.
In a patient (family 5) with congenital disorder of glycosylation type 2v (CDG2V; 619493), Polla et al. (2021) identified compound heterozygosity for 2 mutations in the EDEM3 gene: a G-T transversion at a canonical splice site (c.853+1G-T, NM_025191.3) in the EDEM3 gene, and a c.1407T-A transversion, resulting in a tyr469-to-ter (Y469X; 610214.0006) substitution. The mutations were found by whole-exome sequencing, and the parents were shown to be mutation carriers. Functional studies were not performed.
For discussion of the c.1407T-A transversion (c.1407T-A, NM_025191.3) in the EDEM3 gene, resulting in a tyr469-to-ter (Y469X) substitution that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type 2v (CDG2V; 619493) by Polla et al. (2021), see 610214.0005.
In an Afghan patient (family 6), born to consanguineous parents, with congenital disorder of glycosylation type 2v (CDG2V; 619493), Polla et al. (2021) identified homozygosity for a 4-bp deletion (c.1382_1385del, NM_025191.3) in the EDEM3 gene, resulting in a frameshift and premature termination (Phe461SerfsTer23). The mutation, which was found by trio exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In a patient (family 7) with congenital disorder of glycosylation type 2v (CDG2V; 619493), Polla et al. (2021) identified compound heterozygosity for 2 mutations in the EDEM3 gene: a c.182A-G transition (c.182A-G, NM_025191.3) in the EDEM3 gene, resulting in an asp61-to-gly (D61G) substitution, and a c.1366G-A transition, resulting in an asp456-to-asn (D456N; 610214.0009) substitution. The mutations were found by whole-exome sequencing. The D61G mutation was inherited from the mother; sequencing in the father was not reported. The D456N mutation was not present in the gnomAD database, and the D61G mutation was present in 6 of 218,508 alleles. Functional studies were not performed.
For discussion of the c.1366G-A transition (c.1366G-A, NM_025191.3) in the EDEM3 gene, resulting in an asp456-to-asn (D456N) substitution, that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type 2v (CDG2V; 619493) by Polla et al. (2021), see 610214.0008.
Hirao, K., Natsuka, Y., Tamura, T., Wada, I., Morito, D., Natsuka, S., Romero, P., Sleno, B., Tremblay, L. O., Herscovics, A., Nagata, K., Hosokawa, N. EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J. Biol. Chem. 281: 9650-9658, 2006. [PubMed: 16431915] [Full Text: https://doi.org/10.1074/jbc.M512191200]
Polla, D. L., Edmondson, A. C., Duvet, S., March, M. E., Sousa, A. B., Lehman, A., CAUSES Study, Niyazov, D., van Dijk, F., Demirdas, S., van Slegtenhorst, M. A., Kievit, A. J. A., and 17 others. Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. Am. J. Hum. Genet. 108: 1342-2349, 2021. [PubMed: 34143952] [Full Text: https://doi.org/10.1016/j.ajhg.2021.05.010]
Sood, R., Bonner, T. I., Makalowska, I., Stephan, D. A., Robbins, C. M., Connors, T. D., Morgenbesser, S. D., Su, K., Faruque, M. U., Pinkett, H., Graham, C., Baxevanis, A. D., Klinger, K. W., Landes, G. M., Trent, J. M., Carpten, J. D. Cloning and characterization of 13 novel transcripts and the human RGS8 gene from the 1q25 region encompassing the hereditary prostate cancer (HPC1) locus. Genomics 73: 211-222, 2001. [PubMed: 11318611] [Full Text: https://doi.org/10.1006/geno.2001.6500]