Function (from uniprot)

Adds the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man₇GlcNAc₂) required for protein glycosylation.

Diseases

Defects in ALG12 are the cause of congenital disorder of glycosylation type 1G (CDG1G) [MIM:  ]. CDGs are a family of severe inherited diseases caused by a defect in protein N-glycosylation. They are characterized by under-glycosylated serum proteins. These multisystem disorders present with a wide variety of clinical features, such as disorders of the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.

High impact information on ALG12

• Knowledge of this pathway is important because defects in the glycosyltransferases (Alg1-Alg12 and others not yet identified), which make dolichol-PP-glycans, lead to numerous congenital disorders of glycosylation [1].
• In the patient's fibroblasts, the biosynthetic intermediate GlcNAc(2)Man(7) oligosaccharide was detected both on the lipid carrier dolichyl pyrophosphate and on newly synthesized glycoproteins, thus pointing to a defect in the dolichyl pyrophosphate-GlcNAc(2)Man(7)-dependent ALG12 alpha1,6 mannosyltransferase [2].
• Analysis of the ALG12 cDNA in the CDG patient revealed compound heterozygosity for two point mutations that resulted in the amino acid substitutions T67M and R146Q, respectively [2].
• Subsequent experiments showed that the frequency of gene conversion at the ALG12 locus, in the absence of selection, was 0.25% [3].
• Conventional knock-out of ALG12 in a wild-type background gave an identical phenotype to the mariner mutants, and biochemical analysis confirmed that they have the same defect in the N-linked oligosaccharide synthesis pathway [3].

Biological context of ALG12

• ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg [2].

Anatomical context of ALG12

• It has been shown that the condition stems from a homozygous mutation within the human ortholog of yeast ALG12 gene, which encodes a dolichol-P-mannose:Man7GlcNAc2-PP-dolichol alpha,1-6 mannosyltransferase of the endoplasmic reticulum [4].

References