Alternative titles; symbols
HGNC Approved Gene Symbol: KDELR2
Cytogenetic location: 7p22.1 Genomic coordinates (GRCh38) : 7:6,461,089-6,484,152 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p22.1 | Osteogenesis imperfecta, type XXI | 619131 | Autosomal recessive | 3 |
Resident soluble proteins within the lumen of the endoplasmic reticulum (ER) are retained there by virtue of a C-terminal tetrapeptide ER retention signal, commonly lys-asp-glu-leu (KDEL) in mammals. KDELR2 is one of the receptors that cycle between the Golgi apparatus and the ER, returning proteins containing the KDEL signal to the ER (Lewis and Pelham, 1992).
By screening cDNA libraries with a KDELR1 (131235) sequence, followed by 5-prime RACE of a Burkitt lymphoma cell line cDNA library, Lewis and Pelham (1992) cloned KDELR2, which they designated ERD2.2. The deduced 212-amino acid protein contains 7 transmembrane domains and shares 83.5% identity with KDELR1, with most differences between the 2 receptors in the transmembrane spans.
Using degenerate PCR primers designed from a conserved region of KDELR1 to amplify related cDNAs from an erythroleukemia cell line cDNA library, followed by screening a T-cell cDNA library, Hsu et al. (1992) cloned KDELR2, which they called ELP1. The deduced 214-amino acid protein has a calculated molecular mass of 24.6 kD. Northern blot analysis detected a KDELR2 transcript of about 1.2 kb.
Stumpf (2020) mapped the KDELR2 gene to chromosome 7p22.1 based on an alignment of the KDELR2 sequence (GenBank BC071982) with the genomic sequence (GRCh38).
Lewis and Pelham (1992) observed that KDELR2 transfected into COS-7 cells accumulated predominantly in the Golgi complex, but when the receptor was coexpressed with a target protein containing the KDEL ER retention signal, it redistributed to the ER, mirroring the behavior of KDELR1 under the same conditions.
Hsu et al. (1992) found that about half of KDELR1- or KDELR2-transfected COS cells expressed the receptors in a juxtanuclear, Golgi-like pattern, while the remainder showed a reticular, ER-like pattern with nuclear envelope staining. Overexpression of the KDEL receptors led to the ER-like pattern and was associated with the collapse of the Golgi apparatus into the ER, as seen in cells treated with brefeldin A. In addition to the loss of the Golgi apparatus as a distinct organelle, overexpression resulted in redistribution of the Golgi coat protein, beta-COP (COPB; 600959), to the cytosol, addition of complex oligosaccharides to resident ER glycoproteins, and blockage of anterograde traffic. Hsu et al. (1992) concluded that the KDEL receptors provide signals that regulate retrograde traffic between the Golgi and the ER.
In 6 patients from 4 families with osteogenesis imperfecta type XXI (OI21; 619131), van Dijk et al. (2020) identified homozygosity or compound heterozygosity for mutations in the KDELR2 gene (609024.0001-609024.0004) that segregated with disease and were not found in the gnomAD database. Analysis of patient fibroblasts suggested that OI likely occurred because of the inability of HSP47 (SERPINH1; 600943) to bind to mutant KDELR2 and dissociate from collagen type I (see 120150); instead, HSP47 remained bound to collagen molecules extracellularly, disrupting fiber formation.
In 2 Pakistani sibs and a Turkish boy with progressively deforming OI and neurodevelopmental delay, Efthymiou et al. (2021) identified homozygosity for missense mutations in the KDELR2 gene: an R5W substitution (609024.0005) and a Y162C change (609024.0006), respectively. The mutations segregated with disease in each family, and were not found in the gnomAD database.
In a 14-year-old Pakistani boy (P1) with osteogenesis imperfecta type XXI (OI21; 619131), van Dijk et al. (2020) identified homozygosity for a 1-bp duplication (c.448dupC, NM_006854.3) in the KDELR2 gene, causing a frameshift predicted to result in a premature termination codon (His150fsTer24). His unaffected first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. Quantitative PCR analysis revealed severely decreased expression of KDEL2R in patient fibroblasts, and there was also a 2.2-fold reduction in COL1A1 (120150) expression. In addition, patient primary fibroblasts showed reduced intracellular levels of HSP47 (SERPINH1; 600943) and FKBP65 (FKBP10; 607063), along with reduced procollagen type I in culture media. In contrast to the banded collagen fibers of controls observed with electron microscopy, collagen fibrils in cell culture media from patient fibroblasts remained thin and imperfectly folded, and there were increased amounts of HSP47 bound to monomeric and multimeric collagen molecules. The authors suggested that OI likely occurred because of the inability of HSP47 to bind to the mutant KDELR2 and dissociate from collagen type I; instead, HSP47 remained bound to collagen molecules extracellularly, disrupting fiber formation.
In a 38-year-old Dutch woman (P2-1) and her 35-year-old brother (P2-2) with osteogenesis imperfecta type XXI (OI21; 619131), van Dijk et al. (2020) identified homozygosity for a c.34C-G transversion (c.34C-G, NM_006854.3) in the KDELR2 gene, resulting in a his12-to-asp (H12D) substitution at a highly conserved residue. DNA was unavailable from their unaffected consanguineous parents, but an unaffected sister was heterozygous for the H12D variant. The authors also identified compound heterozygosity for H12D and a nonsense mutation in 2 Dutch fetuses (P4-1 and P4-2) with OI21: the second mutation was a c.360G-A transition in KDELR2, resulting in a trp120-to-ter (W120X; 609024.0004) substitution. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in the gnomAD database. Fibroblasts from patient P2-1 showed a 1.7-fold reduction of COL1A1 (120150) expression. In addition, in contrast to the banded collagen fibers of controls observed with electron microscopy, collagen fibrils in cell culture media from P2-1 remained thin and imperfectly folded, and there were increased amounts of HSP47 (SERPINH1; 600943) bound to monomeric and multimeric collagen molecules. The authors suggested that OI likely occurred because of the inability of HSP47 to bind to the mutant KDELR2 and dissociate from collagen type I; instead, HSP47 remained bound to collagen molecules extracellularly, disrupting fiber formation.
In a 43-year-old Spanish man (P3) with osteogenesis imperfecta type XXI (OI21; 619131), van Dijk et al. (2020) identified homozygosity for a c.398C-T transition (c.398C-T, NM_006854.3) in the KDELR2 gene, resulting in a pro133-to-leu (P133L) substitution at a highly conserved residue. The mutation was present in heterozygosity in 1 unaffected brother, but was not found in 2 more unaffected brothers or in the gnomAD database. The patient also had a brother diagnosed with OI, who died at age 28 years due to respiratory insufficiency.
For discussion of the c.360G-A transition (c.360G-A, NM_006854.3) in the KDELR2 gene, resulting in a trp120-to-ter (W120X) substitution, that was found in compound heterozygous state in 2 Dutch fetuses (P4-1 and P4-2) with osteogenesis imperfecta type XXI (OI21; 619131) by van Dijk et al. (2020), see 609024.0002.
In a Pakistani brother and sister with progressively deforming osteogenesis imperfecta and neurodevelopmental delay (OI21; 619131), Efthymiou et al. (2021) identified homozygosity for a c.13C-T transition (c.13C-T, NM_006854.3) in the KDELR2 gene, resulting in an arg5-to-trp (R5W) substitution at a highly conserved residue within the first transmembrane domain. Their consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database.
In a 4-year-old Turkish boy with progressively deforming osteogenesis imperfecta and neurodevelopmental delay (OI21; 619131), Efthymiou et al. (2021) identified homozygosity for a c.485A-G transition (c.485A-G, NM_006854.3) in the KDELR2 gene, resulting in a tyr162-to-cys (Y162C) substitution at a highly conserved residue within the sixth transmembrane domain. His consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database.
Efthymiou, S., Herman, I., Rahman, F., Anwar, N., Maroofian, R., Yip, J., Mitani, T., Calame, D. G., Hunter, J. V., Sutton, V. R., Yilmaz Gulec, E., Duan, R., and 10 others. Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. (Letter) Am. J. Med. Genet. 185A: 2241-2249, 2021. [PubMed: 33964184] [Full Text: https://doi.org/10.1002/ajmg.a.62221]
Hsu, V. W., Shah, N., Klausner, R. D. A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1. Cell 69: 625-635, 1992. [PubMed: 1316805] [Full Text: https://doi.org/10.1016/0092-8674(92)90226-3]
Lewis, M. J., Pelham, H. R. B. Sequence of a second human KDEL receptor. J. Molec. Biol. 226: 913-916, 1992. [PubMed: 1325562] [Full Text: https://doi.org/10.1016/0022-2836(92)91039-r]
Stumpf, A. M. Personal Communication. Baltimore, Md. 12/18/2020.
van Dijk, F. S., Semler, O., Etich, J., Kohler, A., Jimenez-Estrada, J. A., Bravenboer, N., Claeys, L., Riesebos, E., Gegic, S., Piersma, S. R., Jimenez, C. R., Waisfisz, Q., and 26 others. Interaction between KDELR2 and HSP47 as a key determinant in osteogenesis imperfecta caused by bi-allelic variants in KDELR2. Am. J. Hum. Genet. 107: 989-999, 2020. [PubMed: 33053334] [Full Text: https://doi.org/10.1016/j.ajhg.2020.09.009]