Human β‐mannosidosis: a 3‐year‐old boy with speech impairment and emotional instability

Poënaru, Livia; Akli, Said; Rocchiccioli, F.; Eydoux, Fatrica; Zamet, P

doi:10.1111/j.1399-0004.1992.tb03408.x

Cited by 33 publications

(11 citation statements)

References 13 publications

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“…As a result, they would completely demolish the enzyme activity. In fact, patients with Y126X [7], W192X [14], W231X [38], V321X [39] and Y485X [9] truncations showed typical severe phenotypes such as mental retardation, hearing loss and some degrees of angiokeratomas, with the age of onset ranging from infantile to 18 months [15,40]. Figure 3 provides an overview of the correlation between genotypic variations and phenotypic expressions amongst truncations obtained by mapping the extent of truncated protein in each case, caused by nonsense, insertion and deletion mutations within the MANBA gene sequence, to the human β-mannosidase protein chain.…”

Section: Resultsmentioning

confidence: 99%

A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlation

2011

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BackgroundLysosomal β-D-mannosidase is a glycosyl hydrolase that breaks down the glycosidic bonds at the non-reducing end of N-linked glycoproteins. Hence, it is a crucial enzyme in polysaccharide degradation pathway. Mutations in the MANBA gene that codes for lysosomal β-mannosidase, result in improper coding and malfunctioning of protein, leading to β-mannosidosis. Studying the location of mutations on the enzyme structure is a rational approach in order to understand the functional consequences of these mutations. Accordingly, the pathology and clinical manifestations of the disease could be correlated to the genotypic modifications.ResultsThe wild-type and inherited mutations of β-mannosidase were studied across four different species, human, cow, goat and mouse employing a previously demonstrated comprehensive homology modeling and mutational mapping technique, which reveals a correlation between the variation of genotype and the severity of phenotype in β-mannosidosis. X-ray crystallographic structure of β-mannosidase from Bacteroides thetaiotaomicron was used as template for 3D structural modeling of the wild-type enzymes containing all the associated ligands. These wild-type models subsequently served as templates for building mutational structures. Truncations account for approximately 70% of the mutational cases. In general, the proximity of mutations to the active site determines the severity of phenotypic expressions. Mapping mutations to the MANBA gene sequence has identified five mutational hot-spots.ConclusionAlthough restrained by a limited dataset, our comprehensive study suggests a genotype-phenotype correlation in β-mannosidosis. A predictive approach for detecting likely β-mannosidosis is also demonstrated where we have extrapolated observed mutations from one species to homologous positions in other organisms based on the proximity of the mutations to the enzyme active site and their co-location from different organisms. Apart from aiding the detection of mutational hotspots in the gene, where novel mutations could be disease-implicated, this approach also provides a way to predict new disease mutations. Higher expression of the exoglycosidase chitobiase is said to play a vital role in determining disease phenotypes in human and mouse. A bigger dataset of inherited mutations as well as a parallel study of β-mannosidase and chitobiase activities in prospective patients would be interesting to better understand the underlying reasons for β-mannosidosis.

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Section: Resultsmentioning

confidence: 99%

A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlation

2011

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“…In humans, the clinical symptoms are peripheral neuropathy [14,26], speech impairment [27], epileptic encephalopathy [28], angio keratoma [29], facial dysmorphism [30], and low MANB activity was reported in fibroblast, plasma, and leukocytes [31].…”

Section: Introductionmentioning

confidence: 99%

Novel synthesis of mannosamine conjugated magnetic nanoparticles for purification and stabilization of human lysosomal β-mannosidase

Samra

Athar

2009

Biotechnol Bioproc E

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Human β-mannosidase (MANB) was purified to homogeneity directly from lysosomes by using mannosamine conjugated magnetic (Fe 3 O 4 ) nanoparticles, DE-52 cellulose, and sephadex G-200 chromatography. Fe 3 O 4 nanoparticles were synthesized and utilized ammonia to attach the amino group on the nanoparticles. The particles were covalently attached with Dmannosamine by cross linker glutaraldehyde and confirmed by FTIR spectroscopy. In FTIR analysis, the peaks appeared at 2,356.6 cm −1 for −N = CH linkage and at 3,378.4 cm −1 , 3,664.9 cm −1 for −OH groups confirmed the conjugation of Dmannosamine with Fe 3 O 4 nanoparticles. Results showed a single band of 97 kDa of purified MANB in SDS-PAGE. The isoelectric point was 4.5 and the K m and Vã~ñ values were 2.51 mM and 0.315 μM/min/mg, respectively. The purification fold was 329 with 68% yield. The optimal activity was at pH 5.0 and 75% activity was stable in 20% glycerol at 4 o C. The enzyme activity was inhibited by Ni 2+ , Zn 2+ , Cd 2+ , Cu 2+ , Mo 2+ , Ag +1 , iodoacetate, SDS, DMF, DMSO, ethanol, and acetone; slightly reduced by Pb 2+ , Co 2+ , EDTA, DTT, and β-mercaptoethanol. The activity was not affected by Mg 2+ , Mn 2+ , Sn 2+ , Ca 2+ , Fe 3+ , PMSF, Triton X-100, D-mannosamine, D-mannose, D-mannitol, D-glucose, and D-fructose. The homogeneity of MANB enzyme was further confirmed by 2D-PAGE and immunoblot. This is the first novel report of conjugation of Dmannosamine with Fe 3 O 4 nanoparticles for purification of human MANB enzyme. © KSBB hÉóïçêÇëW=j~ååçë~ãáåÉI=ã~ÖåÉíáÅ=å~åçé~êíáÅäÉëI=cqfoI=ïÉëíÉêå=ÄäçíI=OaJm^db

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“…The first cases of b-mannosidosis were described in 1986 [9,14]. b-mannosidosis is most commonly associated with mental retardation, behavioral problems including hyperactivity and aggressiveness, developmental delay, frequent infections, and hearing loss [14][15][16][17][18][19][20][21][22][23]. Speech impairment, swallowing difficulties, poor muscle tone (hypotonia), reduced sensation, or other nervous system abnormalities have also been reported.…”

Section: Introductionmentioning

confidence: 99%

The structure of mammalian β‐mannosidase provides insight into β‐mannosidosis and nystagmus

Gytz

Liang

et al. 2019

The FEBS Journal

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β‐Mannosidase is a lysosomal enzyme from the glycosyl hydrolase family 2 that cleaves the single β(1–4)‐linked mannose at the nonreducing end of N‐glycosylated proteins, and plays an important role in the polysaccharide degradation pathway. Mutations in the MANBA gene, which encodes the β‐mannosidase, can lead to the lysosomal storage disease β‐mannosidosis, as well as nystagmus, an eye condition characterized by involuntary eye movements. Here, we present the first structures of a mammalian β‐mannosidase in both the apo‐ and mannose‐bound forms. The structure is similar to previously determined β‐mannosidase structures with regard to domain organization and fold, however, there are important differences that underlie substrate specificity between species. Additionally, in contrast to most other ligand‐bound β‐mannosidases from bacterial and fungal sources where bound sugars were in a boat‐like conformation, we find the mannose in the chair conformation. Evaluation of known disease mutations in the MANBA gene provides insight into their impact on disease phenotypes. Together, these results will be important for the design of therapeutics for treating diseases caused by β‐mannosidase deficiency. Database Structural data are available in the Protein Data Bank under the accession numbers http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6DDT and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6DDU.

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Human β‐mannosidosis: a 3‐year‐old boy with speech impairment and emotional instability

Cited by 33 publications

References 13 publications

A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlation

A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlation

Novel synthesis of mannosamine conjugated magnetic nanoparticles for purification and stabilization of human lysosomal β-mannosidase

The structure of mammalian β‐mannosidase provides insight into β‐mannosidosis and nystagmus

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