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

Abstract

BackgroundAlpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities.MethodsTo study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups.Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis.Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant.ResultsComplete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein.ConclusionOur results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein.

Hearing impairment as an early sign of alpha‐mannosidosis in children with a mild phenotype: Report of seven new cases

“…Results from studies suggesting a putative genotype–phenotype correlation remain controversial (Malm & Nilssen, ). However, a recent study of 66 patients showed that MAN2B1 genotypes that allow the encoded mutant enzyme to enter the lysosomes are correlated with certain clinical and biochemical features including better cognitive function, coordination and balance, and lower concentrations of oligosaccharides in the cerebrospinal fluid (Borgwardt et al, ). Because of the rarity of the disease and the relative lack of specific clinical signs, in particular in the early phase of later onset forms, the diagnosis of AM can be challenging and is probably overlooked in a number of cases.…”

Evolution of protein N-glycosylation process in Golgi apparatus which shapes diversity of protein N-glycan structures in plants, animals and fungi

“…The clade close to the group GMII contains genes encoding vacuolar α-mannosidases (YGL156w in yeast, and ENSG00000140400 in human, as shown in Supplementary Figure S8, Clade II)6263. In another major clade, genes were only present in plants and animals, which likely encode α-mannosidases hydrolyzing terminal non-reducing α-D-mannose residues6465.…”

The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis

“…The effects of baseline characteristics on effectiveness will be evaluated by means of regression/ logistic models. Covariates in the model will be age (< 18 and ≥ 18 years), sex (male, female), sibships, genotype (Groups 1, 2, and 3, per Borgwardt et al) [18], residual enzymatic activity (< 10, 10 to < 15, and ≥ 15 nmol/h/mg), and Childhood Health Assessment Questionnaire Disability Index (0-1, 1-2, and 2-3).…”