Alternative titles; symbols
HGNC Approved Gene Symbol: LMAN1
Cytogenetic location: 18q21.32 Genomic coordinates (GRCh38): 18:59,327,823-59,359,265 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.32 | Combined factor V and VIII deficiency | 227300 | Autosomal recessive | 3 |
MR60 is a membrane mannose-specific lectin identified in intracellular compartments of HL60 cells. MR60 is identical to ERGIC53, a protein marker of the intermediate compartment shuttling between the endoplasmic reticulum (ER) and the cis-Golgi apparatus whose cDNA was cloned by Schindler et al. (1993). The 510-amino acid ERGIC53 protein has a calculated molecular mass of 54 kD and contains a N-terminal signal sequence, a transmembrane segment, and a short cytoplasmic domain with an ER retention motif.
Neve et al. (2003) found that the N-terminal carbohydrate recognition domains of ERGIC53, VIPL (LMAN2L; 609552), and VIP36 (LMAN2; 609551) are highly conserved, particularly the motifs required for Ca(2+) and mannose binding and the 2 cysteines predicted to be disulfide bonded. The 3 proteins all have C-terminal ER retrieval motifs. Northern blot analysis detected 6.0- and 2.3-kb ERGIC53 transcripts in all tissues examined, with highest expression in skeletal muscle, kidney, liver, and placenta.
The finding by Nichols et al. (1998) that mutations in ERGIC53 cause combined factors V and VIII deficiency (F5F8D1; 227300) (see MOLECULAR GENETICS) suggested that ERGIC53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.
Nichols and Ginsburg (1999) stated that the identification of ERGIC53 as a component of the ER-Golgi transport machinery that is required for the efficient export of coagulation factors V and VIII was the first demonstration of a cargo-specific pathway for protein export from the ER in mammalian cells. However, the apparently normal levels observed in F5F8D patients for most other plasma proteins demonstrated that ERGIC53 is not essential for the integrity of the intermediate compartment or the more general process of protein export. Nichols and Ginsburg (1999) suggested that the identification of the genetic defect in the subset of patients with F5F8D but with intact ERGIC53 may unmask additional critical components of this unique transport pathway.
Correctly folded proteins destined for secretion are packaged in the endoplasmic reticulum into COPII-coated vesicles (Schekman and Orci, 1996), which subsequently fuse to form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). An alternative mechanism involves selective packaging of secreted proteins with the help of specific cargo receptors. The latter model would be consistent with mutations in LMAN1 causing a selective block to export of factor V and factor VIII. Approximately 30% of individuals with F5F8D have normal levels of LMAN1, suggesting that mutations in another gene may also be associated with F5F8D. Zhang et al. (2003) showed that inactivating mutations in the MCFD2 gene (607788) cause F5F8D (F5F8D2; 613625) with a phenotype indistinguishable from that caused by mutations in LMAN1. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggested that a complex of MCFD2-LMAN1 forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins, including factors V and VIII.
By fractionation and Western blot analyses in HepG2 cells, Mitrovic et al. (2008) showed that SURF4 (185660) interacted with p25 (TMED9; 620436) and ERGIC53 to form heterooligomeric complexes. Knockdown of SURF4 alone had no effect on ER, ERGIC, Golgi, and protein secretion in HeLa cells. However, knockdown of both SURF4 and ERGIC53 disrupted the Golgi apparatus. Likewise, knockdown of p25 disrupted Golgi structure in a manner indistinguishable from that following knockdown of SURF4 and ERGIC53. Morphologic, biochemical, and live-cell imaging analyses indicated that silencing of these cargo receptors destabilized ERGIC without initial impairment of ER exit sites or overall protein secretion. Moreover, the morphologic changes of the Golgi were unlikely to be due to impaired binding of matrix proteins to Golgi membranes, as Golgi matrix proteins remained associated with the dispersed Golgi in knockdown cells. Further analysis revealed that SURF4/ERGIC53 and p25 were required for coat protein I (COPI; see 601924) recruitment to membranes of the early secretory pathway, as silencing SURF4 and ERGIC53 or p25 led to partial dissociation of COPI.
Arar et al. (1996) mapped the human LMAN1 gene by isotopic in situ hybridization to 18q21.3-q22.
Gross (2021) mapped the LMAN1 gene to chromosome 18q21.32 based on an alignment of the LMAN1 sequence (GenBank BC032330) with the genomic sequence (GRCh38).
Nichols et al. (1998) mapped the LMAN1 gene to a YAC and BAC contig containing the critical region for combined factors V and VIII deficiency (F5F8D1; 227300), an autosomal recessive bleeding disorder. DNA sequence analysis identified 2 different mutations, accounting for all affected individuals in 9 families studied. Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the 2 mutations demonstrated complete lack of expression of the mutated gene in these cells. These findings suggested that ERGIC53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.
Neerman-Arbez et al. (1999) performed SSCP and sequence analyses of the ERGIC53 gene in 35 F5F8D families of different ethnic origins. They identified 13 distinct mutations accounting for 52 of 70 mutant alleles. These were 3 splice site mutations, 6 insertions and deletions resulting in translational frameshifts, 3 nonsense codons, and elimination of the translation initiation codon. These mutations were predicted to result in synthesis of either a truncated protein product or no protein at all. The study revealed that F5F8D shows extensive allelic heterogeneity and that all ERGIC53 mutations resulting in F5F8D are 'null.' Approximately 26% of the mutations had not been identified, suggesting that lesions in regulatory elements or severe abnormalities within the introns may be responsible for the disease in these individuals. In 2 such families, Neerman-Arbez et al. (1999) found that ERGIC53 protein was detectable at normal levels in patients' lymphocytes, raising the further possibility of defects at other genetic loci.
Nichols et al. (1999) analyzed 19 additional families by direct sequence analysis of the entire coding region and the intron/exon junctions of the ERGIC53 gene. Seven novel mutations were identified in 10 families, with 1 additional family found to harbor 1 of the 2 previously described mutations. All of the identified mutations would be predicted to result in complete absence of functional ERGIC53 protein. In 8 of the 19 families, no mutation was identified. Genotyping data indicated that at least 2 of these families were not linked to the ERGIC53 locus. These results, like those of Neerman-Arbez et al. (1999), suggested that a significant subset of combined factors V and VIII deficiency is due to mutation in 1 or more additional genes.
Zhang et al. (2008) identified 5 different homozygous mutations in the LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6 families with combined factor V and VIII deficiency. The families were of Turkish, Iraqi, Iranian, and Italian descent.
Genetic linkage studies by Nichols et al. (1997) identified 2 distinct haplotypes segregating with combined factors V and VIII deficiency (227300), suggesting the possibility of 2 independent founder chromosomes. Five Sephardic Jewish families shared 1 haplotype and 4 Middle Eastern Jewish families shared a different haplotype. The data suggested that the origin of the mutation in the Middle Eastern Jewish families may have been more ancient than that in the Sephardic Jewish families. Nichols et al. (1998) found that the Middle Eastern Jewish patients were homozygous for a G insertion in a run of 4 G's corresponding to basepairs 86 to 89 of the ERGIC53 cDNA. The single basepair insertion predicted a frameshift at codon 30, resulting in a truncated protein containing only the first 30 N-terminal amino acids of ERGIC53, followed by 71 residues in the new reading frame leading up to the first stop codon. Analysis of an additional Middle Eastern Jewish family originally from Iran, not included in the original linkage report (Nichols et al., 1997), again identified homozygosity for the G-insertion mutation in the affected individual, with both parents shown to be heterozygous carriers.
Nichols et al. (1998) found that all 6 individuals with F5F8D (227300) from 5 Sephardic Jewish families were homozygous for a splice donor mutation: a thymine-to-cytosine substitution at position 2 of the intron following codon 383, changing the highly conserved splice donor consensus, GT to GC. Analysis of RT-PCR product in the patient was consistent with complete failure to splice this intron. The predicted translation product from the mutant allele contained the N-terminal 383 (of 510) amino acids of ERGIC53 followed by 18 residues encoded by the unspliced intron leading up to the first in-frame stop codon.
In 2 sibs, born of consanguineous Turkish parents, with combined factor V and factor VIII deficiency (227300), Zhang et al. (2008) identified a homozygous 1-bp deletion (795delC) in exon 8 of the LMAN1 gene, resulting in a frameshift and premature termination.
In 2 affected sibs from an Iraqi Chaldean family with combined factor V and factor VIII deficiency (227300), Zhang et al. (2008) identified a homozygous 1-bp deletion (1356delC) in exon 11 of the LMAN1 gene, resulting in a frameshift and premature termination.
In 2 Italian sibs with combined factor V and factor VIII deficiency (227300), Zhang et al. (2008) identified a homozygous 2T-C transition in the LMAN1 gene, resulting in a met1-to-thr (M1T) substitution.
Arar, C., Mignon, C., Mattei, M.-G., Monsigny, M., Roche, A.-C., Legrand, A. Mapping of the MR60/ERGIC-53 gene to human chromosome 18q21.3-18q22 by in situ hybridization. Mammalian Genome 7: 791-792, 1996. [PubMed: 8854877] [Full Text: https://doi.org/10.1007/s003359900238]
Gross, M. B. Personal Communication. Baltimore, Md. 12/7/2021.
Mitrovic, S., Ben-Tekaya, H., Koegler, E., Gruenberg, J., Hauri, H. P. The cargo receptors Surf4, endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-53, and p25 are required to maintain the architecture of ERGIC and Golgi. Molec. Biol. Cell 19: 1976-1990, 2008. [PubMed: 18287528] [Full Text: https://doi.org/10.1091/mbc.e07-10-0989]
Neerman-Arbez, M., Johnson, K. M., Morris, M. A., McVey, J. H., Peyvandi, F., Nichols, W. C., Ginsburg, D., Rossier, C., Antonarakis, S. E., Tuddenham, E. G. D. Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V-factor VIII deficiency. Blood 93: 2253-2260, 1999. [PubMed: 10090934]
Neve, E. P. A., Svensson, K., Fuxe, J., Petterson, R. F. VIPL, a VIP36-like membrane protein with a putative function in the export of glycoproteins from the endoplasmic reticulum. Exp. Cell Res. 288: 70-83, 2003. [PubMed: 12878160] [Full Text: https://doi.org/10.1016/s0014-4827(03)00161-7]
Nichols, W. C., Ginsburg, D. From the ER to the Golgi: insights from the study of combined factors V and VIII deficiency. Am. J. Hum. Genet. 64: 1493-1498, 1999. [PubMed: 10330336] [Full Text: https://doi.org/10.1086/302433]
Nichols, W. C., Seligsohn, U., Zivelin, A., Terry, V. H., Arnold, N. D., Siemieniak, D. R., Kaufman, R. J., Ginsburg, D. Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping. J. Clin. Invest. 99: 596-601, 1997. [PubMed: 9045860] [Full Text: https://doi.org/10.1172/JCI119201]
Nichols, W. C., Seligsohn, U., Zivelin, A., Terry, V. H., Hertel, C. E., Wheatley, M. A., Moussalli, M. J., Hauri, H.-P., Ciavarella, N., Kaufman, R. J., Ginsburg, D. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 93: 61-70, 1998. [PubMed: 9546392] [Full Text: https://doi.org/10.1016/s0092-8674(00)81146-0]
Nichols, W. C., Terry, V. H., Wheatley, M. A., Yang, A., Zivelin, A., Ciavarella, N., Stefanile, C., Matsushita, T., Saito, H., de Bosch, N. B., Ruiz-Saez, A., Torres, A., Thompson, A. R., Feinstein, D. I., White, G. C., Negrier, C., Vinciguerra, C., Aktan, M., Kaufman, R. J., Ginsburg, D., Seligsohn, U. ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families. Blood 93: 2261-2266, 1999. [PubMed: 10090935]
Schekman, R., Orci, L. Coat proteins and vesicle budding. Science 271: 1526-1533, 1996. [PubMed: 8599108] [Full Text: https://doi.org/10.1126/science.271.5255.1526]
Schindler, R., Itin, C., Zerial, M., Lottspeich, F., Hauri, H. P. ERGIC-53, a membrane protein of the EWR-Golgi intermediate compartment, carries an ER retention motif. Europ. J. Cell Biol. 61: 1-9, 1993. [PubMed: 8223692]
Zhang, B., Cunningham, M. A., Nichols, W. C., Bernat, J. A., Seligsohn, U., Pipe, S. W., McVey, J. H., Schulte-Overberg, U., de Bosch, N. B., Ruiz-Saez, A., White, G. C., Tuddenham, E. G. D., Kaufman, R. J., Ginsburg, D. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nature Genet. 34: 220-225, 2003. [PubMed: 12717434] [Full Text: https://doi.org/10.1038/ng1153]
Zhang, B., Spreafico, M., Zheng, C., Yang, A., Platzer, P., Callaghan, M. U., Avci, Z., Ozbek, N., Mahlangu, J., Haw, T., Kaufman, R. J., Marchant, K., Tuddenham, E. G. D., Seligsohn, U., Peyvandi, F., Ginsburg, D. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII. Blood 111: 5592-5600, 2008. [PubMed: 18391077] [Full Text: https://doi.org/10.1182/blood-2007-10-113951]