Related Experiment Video
Updated: May 26, 2026
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense
Hilde Monica Frostad Riise Stensland1, Helle Bagterp Klenow, Lam Van Nguyen
1Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North-Norway, Tromsø, Norway. hilde.monica.stensland@unn.no
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.
Insights
Alpha-mannosidosis, a lysosomal storage disorder, is linked to MAN2B1 gene mutations. Researchers identified 96 variants in 130 patients, revealing a common c.2248C>T mutation likely spread by founder effects.
Area of Science:
- Genetics
- Biochemistry
- Rare Diseases
Background:
- Alpha-mannosidosis is a rare lysosomal storage disorder.
- It results from a deficiency in the lysosomal alpha-mannosidase enzyme, encoded by the MAN2B1 gene.
- Understanding the genetic basis and mutation spectrum is crucial for diagnosis and research.
Purpose of the Study:
- To identify and characterize sequence variants in the MAN2B1 gene in alpha-mannosidosis patients.
- To determine the mutation spectrum and frequency of variants in a global cohort.
- To investigate the origin and spread of a common recurrent mutation.
Main Methods:
- Sequence analysis of the MAN2B1 gene in 130 unrelated patients from 30 countries.
- Identification and cataloging of disease-associated sequence variants.
- Haplotype analysis to investigate the origin of the c.2248C>T variant.
- In vitro expression and enzyme activity assays for selected missense mutations.
Main Results:
- Identified 96 disease-associated variants in 130 patients, including 83 novel variants, expanding the known mutation spectrum.
- Characterized 256 of 260 mutant alleles (98.5%), with c.2248C>T (p.Arg750Trp) being the most frequent (27.3% of alleles).
- Haplotype analysis indicated that c.2248C>T arose on a few ancestral haplotypes and spread via founder effects, with distinct haplotype distributions compared to controls.
- Ten missense variants retained some MAN2B1 activity above background, while most were inactive.
Conclusions:
- The study significantly expands the known mutation spectrum of alpha-mannosidosis.
- The recurrent c.2248C>T variant is a major contributor to the disease, likely spread through founder effects.
- Further studies are needed to fully evaluate the pathogenicity of variants with residual enzyme activity.
