The MAN2B1 gene maps to chromosome 19p13.2, where it gives instructions for making an enzyme called alpha-mannosidase. This protein is made up of 1011 amino acids; and weighs about 114 kDa. Alpha-mannosidase is a lysosomal enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. This activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover.
Defects in this enzyme are the cause of Alpha-Mannosidosis, a lysosomal storage disease characterized by accumulation of unbranched oligosaccharide chains. The symptoms of this disease range widely in their onset and severity, and may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and dysfunction of the immune system.
The MAN2B1 gene consists of 24 coding exons, and spans approximately 20 kb in the genomic DNA. At least 70 different mutations in this gene have been identified in patients with alpha-mannosidosis. These mutations result in accumulation of oligosaccharides in the lysosomes and cause the cells to malfunction and eventually die, resulting in the signs and symptoms of alpha-mannosidosis.
In two sibs with alpha-mannosidosis born of consanguineous parents and originally reported by Bach et al. (1978), Nilssen et al. (1997) identified a homozygous 212A-T transversion in exon 2 of the MANB gene, resulting in a p.H71L substitution. Residue H71 is conserved among lysosomal alpha-mannosidases from several species. The sibs were thought to be mildly affected and residual acidic alpha-mannosidase activity of 20% of normal was detected in the patient's fibroblasts, according to the report of this family by Bach et al. (1978). Nevertheless, the patients showed vacuolated leukocytes and fibroblasts consistent with the disease phenotype. Nilssen et al. (1997) suggested that mutant mannosidase enzymes, even though containing residual activity upon testing at the appropriate pH, may be mislocalized to nonlysosomal compartments and therefore functionally inactive. Later, Gotoda et al. (1998) identified the same mutation, which they designated p.HIS72LEU in keeping with the new codon numbering system. The patient, represented by cell line GM2051, was one of the patients reported by Nilssen et al. (1997).
Al-Jasmi et al. (2013) studied the prevalence of lysosomal storage diseases (LSDs) in the UAE and reported their mutation spectrum. Five Emiratis with Alpha-Mannosidosis, belonging to two separate tribes, were identified in this study. Al-Jasmi et al. (2013) reported a c.2368C>T (p.Q790X) mutation in one of the tribes, and a c.2119C>T (p.Q707X) mutation in the other.