Identification of 83 novel alpha-mannosidosis-associated sequence variants: Functional analysis of MAN2B1 missense mutations

Abstract

The lysosomal storage disorder alpha-mannosidosis is caused by deficiency of the enzyme lysosomal alpha-mannosidase (MAN2B1). In this study, 96 disease-associated sequence variants were identified in 130 unrelated alpha-mannosidosis patients from 30 countries. Eighty-three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T-associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a few ancestral haplotypes where the major haplotype subsequently has spread by founder effects. The disease-associated missense mutations were introduced into the human MAN2B1 cDNA, expressed in cell culture and assayed for MAN2B1 activity. The majority of the variants were inactive, however, ten showed MAN2B1 activity above background, and more detailed studies are necessary to further evaluate the pathogenicity of these variants.

Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation

“…Mutation analysis of the MAN2B1 gene and determination of the subcellular localisation of mutant MAN2B1 protein were performed as described in Riise Stensland et al [11]. Briefly, the 24 MAN2B1 exons, corresponding exon-intron borders and parts of the 5’- and 3’- untranslated regions were sequenced using the Sanger method.…”

“…The mutations are scattered throughout the coding region and include missense mutations, nonsense mutations, frame-shifting small insertions/duplications/deletions, in-frame duplications, intronic splice site mutations and large deletions. In a recent study, 96 alpha-mannosidosis-associated mutations were reported in 130 unrelated patients from 30 countries [11]. Most of these mutations were private, but three mutations, c.2248C>T (p.Arg750Trp), c.1830+1G>C and c.2426 T>C (p.Leu809Pro), were relatively frequent, and accounted for approximately 27 %, 5 % and 3 %, respectively, of the disease alleles [11].…”

“…In a recent study, 96 alpha-mannosidosis-associated mutations were reported in 130 unrelated patients from 30 countries [11]. Most of these mutations were private, but three mutations, c.2248C>T (p.Arg750Trp), c.1830+1G>C and c.2426 T>C (p.Leu809Pro), were relatively frequent, and accounted for approximately 27 %, 5 % and 3 %, respectively, of the disease alleles [11]. …”

“…The molecular basis of alpha-mannosidase deficiency and the phenotype has not previously been studied systematically. However, results from two studies [11, 16] indicated that there was no apparent correlation between mutations and clinical phenotypes.…”

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

“…Moreover, a significant improvement of motor abilities and most notably of cognitive functions was achieved, indicating that our findings in the mouse model can be well assigned to the clinical studies, at least for patients with enzymatically inactive LAMAN variants. Patients lacking expression of LAMAN1, 3, 6 may develop antibodies against the recombinant enzyme affecting ERT efficacy. However, in this first clinical study for alpha‐mannosidosis the frequency of infusion‐related reactions as well as the production of antibodies against the recombinant enzyme was low19 in comparison with other ERT studies 50, 51, 52, 53, 54.…”