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

Borgwardt L, Stensland HM, Olsen KJ, Wibrand F, Klenow HB, Beck M, Amraoui Y, Arash L, Fogh J, Nilssen Ø, Dali CI, Lund AM - Orphanet J Rare Dis (2015)

Bottom Line: 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.P values of <0.05 were considered as statistically significant.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark. line.gutte.borgwardt@regionh.dk.

ABSTRACT

Background: Alpha-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.

Methods: To 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.

Results: Complete 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.

Conclusion: Our 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.

No MeSH data available.


Related in: MedlinePlus

Schematic view of the localisation and type of mutations in the study cohort. Boxes represent exons (coding region in grey), lines represent introns. Mutations are labelled according to HGVS recommendations (http://www.hgvs.org/mutnomen/). Deletions, duplications and splice variants are described using the MAN2B1 coding DNA reference sequence NM_000528.3, where position +1 corresponds to A in the first ATG translation initiation codon. Novel mutations are in bold. Variants of uncertain clinical significance are in italics. *Variant c.1230+5G>A was detected in two siblings where it was in cis with c.2248C>T p.Arg750Trp; variants c.1501T>A p.Cys501Ser and c.2849G>C p.Arg950Pro were in cis in one patient
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Fig1: Schematic view of the localisation and type of mutations in the study cohort. Boxes represent exons (coding region in grey), lines represent introns. Mutations are labelled according to HGVS recommendations (http://www.hgvs.org/mutnomen/). Deletions, duplications and splice variants are described using the MAN2B1 coding DNA reference sequence NM_000528.3, where position +1 corresponds to A in the first ATG translation initiation codon. Novel mutations are in bold. Variants of uncertain clinical significance are in italics. *Variant c.1230+5G>A was detected in two siblings where it was in cis with c.2248C>T p.Arg750Trp; variants c.1501T>A p.Cys501Ser and c.2849G>C p.Arg950Pro were in cis in one patient

Mentions: Disease-associated MAN2B1 mutations were identified in all patients. About half of the unrelated patients were homozygous (28 of 57). In total we detected 56 disease-associated variants, of which 11 were novel (see Tables 1 and 2 and Fig. 1). None of the novel mutations were present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/) but c.2885G>A p.(Arg962His) was present in the large database of exome sequences ExAc (Exome Aggregation Consortium (www. http://exac.broadinstitute.org/)) with a frequency of 2,47e-05 (3 alleles out of 121 374). For 43 patients parental sequencing data were collected, for 7 patients only sequencing data from the mother or the father were collected and for 16 patients the parental samples were not available.Table 1


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

Borgwardt L, Stensland HM, Olsen KJ, Wibrand F, Klenow HB, Beck M, Amraoui Y, Arash L, Fogh J, Nilssen Ø, Dali CI, Lund AM - Orphanet J Rare Dis (2015)

Schematic view of the localisation and type of mutations in the study cohort. Boxes represent exons (coding region in grey), lines represent introns. Mutations are labelled according to HGVS recommendations (http://www.hgvs.org/mutnomen/). Deletions, duplications and splice variants are described using the MAN2B1 coding DNA reference sequence NM_000528.3, where position +1 corresponds to A in the first ATG translation initiation codon. Novel mutations are in bold. Variants of uncertain clinical significance are in italics. *Variant c.1230+5G>A was detected in two siblings where it was in cis with c.2248C>T p.Arg750Trp; variants c.1501T>A p.Cys501Ser and c.2849G>C p.Arg950Pro were in cis in one patient
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4465300&req=5

Fig1: Schematic view of the localisation and type of mutations in the study cohort. Boxes represent exons (coding region in grey), lines represent introns. Mutations are labelled according to HGVS recommendations (http://www.hgvs.org/mutnomen/). Deletions, duplications and splice variants are described using the MAN2B1 coding DNA reference sequence NM_000528.3, where position +1 corresponds to A in the first ATG translation initiation codon. Novel mutations are in bold. Variants of uncertain clinical significance are in italics. *Variant c.1230+5G>A was detected in two siblings where it was in cis with c.2248C>T p.Arg750Trp; variants c.1501T>A p.Cys501Ser and c.2849G>C p.Arg950Pro were in cis in one patient
Mentions: Disease-associated MAN2B1 mutations were identified in all patients. About half of the unrelated patients were homozygous (28 of 57). In total we detected 56 disease-associated variants, of which 11 were novel (see Tables 1 and 2 and Fig. 1). None of the novel mutations were present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/) but c.2885G>A p.(Arg962His) was present in the large database of exome sequences ExAc (Exome Aggregation Consortium (www. http://exac.broadinstitute.org/)) with a frequency of 2,47e-05 (3 alleles out of 121 374). For 43 patients parental sequencing data were collected, for 7 patients only sequencing data from the mother or the father were collected and for 16 patients the parental samples were not available.Table 1

Bottom Line: 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.P values of <0.05 were considered as statistically significant.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark. line.gutte.borgwardt@regionh.dk.

ABSTRACT

Background: Alpha-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.

Methods: To 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.

Results: Complete 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.

Conclusion: Our 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.

No MeSH data available.


Related in: MedlinePlus