Alternative titles; symbols
HGNC Approved Gene Symbol: LMAN2L
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38): 2:96,705,929-96,740,064 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q11.2 | ?Intellectual developmental disorder, autosomal dominant 69 | 617863 | Autosomal dominant | 3 |
| ?Intellectual developmental disorder, autosomal recessive 52 | 616887 | Autosomal recessive | 3 |
The LMAN2L gene encodes a transmembrane protein located at the endoplasmic reticulum (ER) where it functions as a cargo receptor in the transport of glycoproteins (summary by Rafiullah et al., 2016).
Nufer et al. (2003) and Neve et al. (2003) independently cloned LMAN2L, which they both called VIPL, by searching databases using sequences conserved in L-type lectins, followed by screening liver carcinoma cell line and fetal brain cDNA libraries, respectively. The deduced 348-amino acid protein contains an N-terminal signal peptide, followed by a lectin-type carbohydrate recognition domain (CARD), a transmembrane domain, and a C-terminal endoplasmic reticulum (ER) retrieval motif. The CRD has conserved cysteines and key residues required for Ca(2+) and sugar binding, as well as an N-glycosylation site. VIPL shares 35% and 58% amino acid identity with ERGIC53 (LMAN1; 601567) and VIP36 (LMAN2; 609551), respectively, with highest identity in the CARDs.
EST database analysis by Nufer et al. (2003) suggested that VIPL is ubiquitously expressed. VIPL distributed with the membrane pellet of fractionated transfected human embryonic kidney cells. Confocal immunofluorescence microscopy localized VIPL to the ER of HepG2 and all other human cell lines examined. Endoglycosidase treatment indicated that the N-glycan of VIPL is a high-mannose-type carbohydrate.
By Northern blot analysis, Neve et al. (2003) detected a 2.4-kb VIPL transcript in all tissues examined. Expression was highest in skeletal muscle and kidney, intermediate in heart, liver, and placenta, low in brain, thymus, spleen, small intestine, and lung, and very low in colon and peripheral blood lymphocytes. Immunofluorescent microscopy found weak VIPL staining in all cell lines examined. VIPL was expressed in a reticular pattern, including staining of the nuclear rim, suggesting localization to the ER.
Nufer et al. (2003) found that overexpression of VIPL in HepG2 cells led to the redistribution of ERGIC53 from a concentration near the Golgi to the ER. The morphology of the general secretory pathway was unaffected by VIPL overexpression, and mutation analysis indicated that the lectin domain was not required for ERGIC53 redistribution. Retention of VIPL in the ER required a C-terminal RKR motif, and the RKR motif of VIPL was required to redistribute ERGIC53. VIPL lacking the RKR motif localized to the plasma membrane, and its distribution did not overlap with that of ERGIC53.
Neve et al. (2003) also found that ERGIC53 redistributed from the perinuclear Golgi to the ER when VIPL was overexpressed in baby hamster kidney cells, and that mutation of the VIPL ER retrieval signal resulted in transport of VIPL to the cell surface. Neve et al. (2003) found that knockdown of VIPL expression in HeLa cells with small interfering RNA resulted in reduced secretion of a select group of proteins, while the overall pattern of protein secretion was unaffected.
Nufer et al. (2003) determined that the LMAN2L gene contains 8 exons and spans 34.14 kb.
By genomic sequence analysis, Nufer et al. (2003) mapped the LMAN2L gene to chromosome 2q11.2.
Autosomal Recessive Intellectual Developmental Disorder 52
In affected members of a consanguineous Pakistani family with autosomal recessive intellectual developmental disorder-52 (MRT52; 616887), Rafiullah et al. (2016) identified a homozygous missense mutation in the LMAN2L gene (R53Q; 609552.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family.
Autosomal Dominant Intellectual Developmental Disorder 69
In a father and his 3 sons with autosomal dominant intellectual developmental disorder-69 (MRD69; 617863), Alkhater et al. (2019) identified a heterozygous 1-bp deletion in the LMAN2L gene (c.1073delT; 609552.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In affected members of a large consanguineous Pakistani family with autosomal recessive intellectual developmental disorder-52 (MRT52; 616887), Rafiullah et al. (2016) identified a homozygous c.158G-A transition in the LMAN2L gene, resulting in an arg53-to-gln (R53Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The variant was predicted to be located in a domain involved in protein-protein interactions. Patient cells had no evidence of glycosylation defects. Additional functional studies were not performed.
In a father and his 3 sons with autosomal dominant intellectual developmental disorder-69 (MRD69; 617863), Alkhater et al. (2019) identified a heterozygous 1-bp deletion (c.1073delT, NM_001142292.1) in the LMAN2L gene, resulting in a frameshift causing disruption of the KRFY endoplasmic reticulum location motif and a stop codon (Phe358SerfsTer16), replacing the last 2 amino acids of the protein with a new 15-amino acid stretch. The authors showed that the mutation eliminated the ER retention signal and mislocalized the protein to the plasma membrane.
Alkhater, R. A., Wang, P., Ruggieri, A., Israelian, L., Walker, S., Scherer, S. W., Smith, M. L., Minassian, B. A. Dominant LMAN2L mutation causes intellectual disability with remitting epilepsy. Ann. Clin. Transl. Neurol. 6: 807-811, 2019. [PubMed: 31020005] [Full Text: https://doi.org/10.1002/acn3.727]
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]
Nufer, O., Mitrovic, S., Hauri, H.-P. Profile-based data base scanning for animal L-type lectins and characterization of VIPL, a novel VIP36-like endoplasmic reticulum protein. J. Biol. Chem. 278: 15886-15896, 2003. [PubMed: 12609988] [Full Text: https://doi.org/10.1074/jbc.M211199200]
Rafiullah, R., Aslamkhan, M., Paramasivam, N., Thiel, C., Mustafa, G., Wiemann, S., Schlesner, M., Wade, R. C., Rappold, G. A., Berkel, S. Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family. J. Med. Genet. 53: 138-144, 2016. [PubMed: 26566883] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103179]