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ALG11 ALPHA-1,2-MANNOSYLTRANSFERASE; ALG11

ALG11 ALPHA-1,2-MANNOSYLTRANSFERASE; ALG11

Alternative titles; symbolsASPARAGINE-LINKED GLYCOSYLATION 11, S. CEREVISIAE, HOMOLOG OFALG11, S. CEREVISIAE, HOMOLOG OFKIAA0266HGNC Approved Gene Symbol: ALG11C...

Alternative titles; symbols

  • ASPARAGINE-LINKED GLYCOSYLATION 11, S. CEREVISIAE, HOMOLOG OF
  • ALG11, S. CEREVISIAE, HOMOLOG OF
  • KIAA0266

HGNC Approved Gene Symbol: ALG11

Cytogenetic location: 13q14.3 Genomic coordinates (GRCh38): 13:52,012,397-52,033,599 (from NCBI)

▼ Description
ALG11 is a mannosyltransferase that uses GDP-mannose to sequentially add the fourth and fifth mannose residues to growing dolichol-linked oligosaccharide side chains at the outer leaflet of the endoplasmic reticulum (ER). Upon completion, the lipid-linked polyoligosaccharides are translocated to the ER lumen for subsequent transfer to substrate asparagine residues of newly synthesized glycoproteins (Rind et al., 2010).

▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated KG-1 immature myeloid cell line, Nagase et al. (1996) cloned ALG11, which they designated KIAA0266. The transcript contains a repetitive element in its 3-prime end, and the deduced protein contains 766 amino acids. Northern blot analysis revealed low and uniform expression of ALG11 in all human tissues and cell lines examined.

Rind et al. (2010) predicted that human ALG11 contains 2 Rossmann-like type B domains, which are separated by a catalytic flexible hinge region, and a conserved C-terminal nucleotide sugar-binding region. ALG11 also has 2 predicted transmembrane domains and 2 putative N-glycosylation sites. Immunofluorescence analysis of human fibroblasts revealed colocalization of ALG11 with an ER marker, calnexin (CANX; 114217).

▼ Mapping
By radiation hybrid analysis, Nagase et al. (1996) mapped the ALG11 gene to chromosome 13. Hartz (2010) mapped the ALG11 gene to chromosome 13q14.3 based on an alignment of the ALG11 sequence (GenBank AK025456) with the genomic sequence (GRCh37).

▼ Molecular Genetics
In 2 Turkish sibs, born of consanguineous parents, with congenital disorder of glycosylation type Ip (CDG1P; 613661), Rind et al. (2010) identified a homozygous mutation (L86S; 613666.0001) in the ALG11 gene. The phenotype was a multisystem metabolic disorder characterized by hypotonia, seizures, developmental retardation, deafness, and death by age 2 years. One affected child showed mild dysmorphic features.

In 3 unrelated patients with CDG1P, Thiel et al. (2012) identified compound heterozygous or homozygous mutations in the ALG11 gene (613666.0002-613666.0006). All mutations occurred in conserved residues, and the cellular biochemical defects could be rescued by retroviral complementation with wildtype ALG11. Glucose starvation prior to metabolic labeling of patient-derived fibroblasts was a crucial step for the correct biochemical diagnosis.

In 2 unrelated patients with CDG1P, Haanpaa et al. (2019) identified compound heterozygous mutations in the ALG11 gene (see 613666.0007-613666.0009). The mutations, which were identified by whole-exome sequencing or gene-specific deletion/duplication analysis, segregated with the disorder in both families. Haanpaa et al. (2019) found reduced ALG11 protein expression and evidence for a glycosylation defect in fibroblasts from both patients.

▼ ALLELIC VARIANTS ( 9 Selected Examples):

.0001 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, LEU86SER
In 2 Turkish sibs, born of consanguineous parents, with congenital disorder of glycosylation type Ip (CDG1P; 613661), Rind et al. (2010) identified a homozygous 257T-C transition in exon 2 of the ALG11 gene, resulting in a leu86-to-ser (L86S) substitution in a highly conserved region in the N terminus between 2 hydrophobic helices at the end of a glycine-rich motif. Each unaffected parent was heterozygous for the mutation, which was not found in 100 control alleles. Introduction of wildtype ALG11 in patient fibroblasts and yeast deficient in the enzyme complemented the biochemical abnormality. Immunofluorescent studies showed that the mutation did not affect protein localization and did not appear to affect the stability of the mannosyltransferase complex. However, studies in yeast showed that the mutant L86S protein had some residual activity, but not as much as wildtype, suggesting that it is a leaky mutation.

.0002 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, 18-BP DEL, NT623
In a 7-year-old girl with congenital disorder of glycosylation type Ip (CDG1P; 613661), Thiel et al. (2012) identified compound heterozygosity for 2 mutations in the ALG11 gene: an 18-bp deletion (623_642) resulting in a frameshift and premature termination after 210 amino acids, and an 836A-C transversion resulting in a tyr279-to-ser (Y279S; 613666.0003) substitution. The patient had developmental delay, mental retardation, axial hypotonia, slight peripheral hypertonia, no communication and poor social interaction, seizures, and strabismus. Neither mutation was found in 120 control alleles. Biochemical analysis showed a CDG type I pattern. However, the pathologic glycosylation phenotype was only apparent after glucose starvation in patient fibroblasts; then, analysis of dolichol-linked oligosaccharides led to the emergence of pathologic shortened intermediate dolichol-linked oligosaccharides, indicating a defect in biosynthesis which could be rescued by retroviral complementation with wildtype ALG11.

.0003 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, TYR279SER
For discussion of the tyr279-to-ser (Y279S) mutation in the ALG11 gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type Ip (CDG1P; 613661) by Thiel et al. (2012), see 613666.0002.

.0004 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, LEU381SER
In a 4.5-year-old girl with congenital disorder of glycosylation type Ip (CDG1P; 613661), Thiel et al. (2012) identified compound heterozygosity for 2 mutations in the ALG11 gene: a 1142T-C transition resulting in a leu381-to-ser (L381S) substitution, and a 1192G-A transition resulting in a glu398-to-lys (E398K; 613666.0005) substitution. The patient had developmental delay, mental retardation, central hypotonia, peripheral hypertonia, no communication, and seizures. Other anomalies included dystrophic facial features with high forehead, long philtrum, and retrognathia, dry scaly skin, oscillation of body temperature, inverted nipples, fat pads, and scoliosis. Neither mutation was found in 120 control alleles. Biochemical analysis showed a CDG type I pattern. However, the pathologic glycosylation phenotype was only apparent after glucose starvation in patient fibroblasts; then, analysis of dolichol-linked oligosaccharides led to the emergence of pathologic shortened intermediate dolichol-linked oligosaccharides, indicating a defect in biosynthesis which could be rescued by retroviral complementation with wildtype ALG11.

.0005 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, GLU398LYS
For discussion of the glu398-to-lys (E398K) mutation in the ALG11 gene that was found in a patient with congenital disorder of glycosylation type Ip (CDG1P; 613661) by Thiel et al. (2012), see 613666.0004.

.0006 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, GLN318PRO
In an 8.5-year-old boy with congenital disorder of glycosylation type Ip (CDG1P; 613661), Thiel et al. (2012) identified a homozygous 953A-C transversion in the ALG11 gene, resulting in a gln318-to-pro (Q318P) substitution. The patient had developmental delay, mental retardation, no communication, seizures, and strabismus. The mutation was not found in 120 control alleles. Biochemical analysis showed a CDG type I pattern. However, the pathologic glycosylation phenotype was only apparent after glucose starvation in patient fibroblasts; then, analysis of dolichol-linked oligosaccharides led to the emergence of pathologic shortened intermediate dolichol-linked oligosaccharides, indicating a defect in biosynthesis which could be rescued by retroviral complementation with wildtype ALG11.

.0007 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, GLU312GLY
By whole-exome sequencing in a 29-month-old girl (CDG-0455) of mixed European heritage with congenital disorder of glycosylation type Ip (CDG1P; 613661), Haanpaa et al. (2019) identified compound heterozygous mutations in the ALG11 gene: a c.935A-G transition, resulting in a glu312-to-gly (E312G) substitution, and a c.1223T-G transversion, resulting in a met408-to-arg (M408R; 613666.0008) substitution. Each parent was heterozygous for one of the mutations. Neither mutation was present in the gnomAD database. Significant hypoglycosylation of GP130 (600694) was found in patient fibroblasts, supporting the presence of a glycosylation defect, and expression of ALG11 protein was reduced compared to control. Analysis of lipid-linked oligosaccharide glycans in patient fibroblasts was consistent with a diagnosis of CDG1P.

.0008 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, MET408ARG
For discussion of the c.1223T-G transversion in the ALG11 gene, resulting in a met408-to-arg (M408R) substitution, that was found in compound heterozygous state in a child with congenital disorder of glycosylation type Ip (CDG1P; 613661) by Haanpaa et al. (2019), see 613666.0007.

.0009 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ip
ALG11, LEU46PRO
In a 14-year-old Hispanic boy (CDG-0358) with congenital disorder of glycosylation type Ip (CDG1P; 613661), Haanpaa et al. (2019) identified compound heterozygous mutations in the ALG11 gene: a maternally inherited c.137T-C transition, resulting in a leu46-to-pro (L46P) substitution, and a paternally inherited deletion of the entire ALG11 gene. The missense mutation was identified by whole-exome sequencing and the deletion by gene deletion/duplication analysis. The L46P mutation was reported in only 1 of 251,4448 alleles in the gnomAD database. Significant hypoglycosylation of GP130 (600694) was found in patient fibroblasts, supporting the presence of a glycosylation defect, and expression of ALG11 protein was reduced compared to control. Analysis of lipid-linked oligosaccharide glycans was consistent with a diagnosis of CDG1P.

Tags: 13q14.3