Human [beta]-mannosidase cDNA characterization and first identification of a mutation associated with human [beta]-mannosidosis
Human [beta] -mannosidase cDNA characterization and first identification of a mutation associated with human [beta]-mannosidosisAisha H. Alkhayat1, Stacey A. Kraemer1, Jeffrey R. Leipprandt1, Milan Macek2, Wim J. Kleijer3 and Karen H. Friderici1,*
1Department of Pathology, Michigan State University, East Lansing, MI 48824, USA, 2Department of Medical Genetics II, Charles University Hospital Motol, Prague, Czech Republic and 3Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands
Received August 20, 1997;Revised and Accepted October 12, 1997
DDBJ/EMBL/GenBank accession no. U60337
Human [beta]-mannosidosis is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme [beta]-mannosidase. Unlike the severe clinical manifestation of the disease in ruminants, in which it leads to neonatal death, the human disease phenotype is generally milder. In addition, the phenotypic manifestation among the reported cases of human [beta]-mannosidosis is variable, even among members of the same family. To understand the molecular basis of the human disease and the mechanisms for such clinical variability, we sequenced the entire coding region of the human [beta]-mannosidase gene using a combination of cDNA library screening, RT-PCR and 5' rapid amplification of cDNA ends (RACE). The composite cDNA is 3293 nt, consisting of an 87 nt 5'-untranslated region, 2640 nt coding region and 566 nt 3'-untranslated region. The gene was localized to human chromosome 4q22-25. Analysis of a multiple tissue northern blot demonstrated a single 3.7 kb transcript. Mutation analysis of a Czech gypsy family with two siblings differently affected with [beta]-mannosidosis demonstrated a homozygous A -> G transition 2 bp upstream of a splice acceptor site. The associated cryptic splice site activation and exon skipping caused by this mutation resulted in two abnormally spliced mutant mRNA species in both siblings.
Lysosomal [beta]-D-mannosidase (EC 3.2.1.25) is the final exoglycosidase in the degradation pathway for N-linked oligosaccharide moieties of glycoproteins. The enzyme cleaves the [beta]-mannoside linkage of the disaccharide Man- ([beta]1 -> 4)GlcNAc. Genetic deficiency of this enzyme activity results in pathological manifestation of the lysosomal storage disease [beta]-mannosidosis (McKusick, MIM 248510), which is characterized by accumulation and excretion of undegraded storage products containing [beta]1 -> 4 linkages.
[beta]-Mannosidosis in Nubian goats (1 -4 ) and in Salers cattle (5 -7 ) consistently manifests as a severe neonatal neurological disorder. The affected animals display facial dysmorphism, contractures and hyperextension of the limb joints, nystagmus, intention tremors and, in affected goats, deafness (5 -9 ). Thereare primarily two storage products, the trisaccharide Man([beta]1 -> 4)GlcNAc([beta]1 -> 4)GlcNAc and the disaccharide Man([beta]1 -> 4)GlcNAc (4 ,8 ,10 -13 ). The mutations associated with [beta]-mannosidosis in cattle (K.H.Friderici and J.R.Leipprandt, unpublished results) and goats (14 ) both cause premature termination of translation.
Unlike the ruminant disease, human [beta]-mannosidosis is generally milder and heterogeneous in its clinical spectrum, with a wide range of symptoms and age of onset. Among the 13 cases reported since 1986 (15 -24 ) it is still difficult to distinguish a consistent pattern of clinical manifestation for [beta]-mannosidosis, possibly due in part to the occurrence of different mutant alleles at the [beta]-mannosidase locus. The disease is associated with a range of neurological involvement, including various degrees of mental retardation except for two cases (22 ,23 ), hearing loss and speech impairment (16 ,18 ,19 ,21 ), hypotonia (18 ,19 ,24 ), epilepsy (17 ) and peripheral neuropathy (22 ). There is no evidence for severe dysmyelination, as seen in caprine and bovine [beta]-mannosidosis. Other clinical symptoms of [beta]-mannosidosis patients are angiokeratomata (16 ,23 ), susceptibility to upper and lower respiratory tract infections (18 ,19 ,24 ), facial dysmorphism (15 ,19 ,20 ) and skeletal abnormalities (15 ,19 ). Dermal fibroblasts (22 ,23 ,25 ), bone marrow (19 ) and endothelial cells (23 ) from these patients show cytoplasmic vacuolation. Unlike ruminants, the primary storage and urinary excretion product in humansis the disaccharide Man([beta]1 -> 4)GlcNAc (25 ,26 ). Affected individuals have a profound reduction in [beta]-mannosidase activity in plasma, fibroblasts and leukocytes.
Screening of a [lambda]ZAPII human placental cDNA library with probe hu 82/89 (see Materials and Methods) resulted in identification of three independent clones, pHUBM3, pHUBM7 and pHUBM8, with 1.9, 1.15 and 1.49 kb inserts respectively (Fig. 1 b). The three clones overlapped and contained a putative stop codon analogous to the stop codon in the bovine cDNA sequence. However, two of the clones, pHUBM3 and pHUBM7, were chimeras with other human cDNA sequences (Fig. 1 b). The third clone, pHUBM8, showed 80% sequence identity with the 3'-end of the coding sequence of bovine [beta]-mannosidase cDNA and less homology following the stop codon. The human sequence has a 38 nt insertion, after which the homology at the 3'-untranslated region (UTR) drops to ~73%, with additional stretches of insertions and deletions. To complete the human [beta]-mannosidase cDNA sequence RT-PCR and 5' RACE were performed using cDNA synthesized from human placenta total RNA and primers based upon the cloned bovine and human sequences (Fig. 1 c and d and Table 1 ).
The composite human [beta]-mannosidase cDNA (GenBank accession no. U60337), sequenced in both directions, is 3293 nt and contains an 87 nt 5'-UTR, 2640 nt encoding 879 amino acids and a 566 nt 3'-UTR (Fig. 2 ). The predicted translation initiation codon (27 ), at nt 88, was assigned based upon homology to the bovine and caprine initiation sites. Heterozygosity in the placental RNA was found at nt 844, corresponding to a deduced amino acid codon of valine, homologous to the bovine peptide, or an isoleucine. Eight potential glycosylation sites were found in the predicted amino acid sequence (Fig. 2 ). Three consensus sequences for polyadenylation were found in pHUBM8, at positions 2762, 3138 and 3263. The AAUAAA sequence at position 3263 was followed by a 12 base poly(A) stretch.
Northern blot analysis of poly(A)+ RNA isolated from various human tissues using the hu 82/89 probe revealed a unique 3.7 kb transcript which was expressed in all the tested tissues, albeit at varying levels (Fig. 3 A). After the hybridization signals were normalized to the mRNA levels of [beta]-actin (data not shown), [beta]-mannosidase mRNA was found to be most highly expressed in pancreas, followed by placenta and kidney, with lower expression levels found in liver, lung, brain, heart and muscle (Fig. 3 B). Overexposure of the blot showed no evidence of any alternative, weakly hybridizing transcripts in any of the tissues studied (Fig. 3 A).
To verify previous assignments of the human [beta]-mannosidase gene to chromosome 4 (28 ,29 ) and to more narrowly define the chromosomal localization, a PCR test that specifically amplifies human genomic [beta]-mannosidase DNA but not rodent DNA was developed. Amplification of DNA from a panel of somatic cell hybrid lines in which human chromosomes 1-22, X and Y were individually retained produced the predicted size DNA fragment only in the cell line that contained human chromosome 4 (data not shown). To further localize and identify the chromosomal region containing the [beta]-mannosidase gene, this same test was conducted on a series of somatic cell hybrid lines harboring various deletions in overlapping regions of human chromosome 4 (Fig. 4 ). The presence of the diagnostic PCR product in NA10115, NA11447 and NA13402, but not in NA11449 or NA13396, localized the human [beta]-mannosidase gene to 4q21-25.
abp positions are relative to 5'-end of human cDNA sequence. bBB is bovine [beta]-mannosidase sequence-based primer. cBH is human [beta]-mannosidase sequence-based primer.
To identify the molecular defect causing [beta]-mannosidosis in a Czech family reported by Kleijer et al. (19 ) we analyzed RNA from two affected siblings, their heterozygous sister and their parents. The entire coding region of [beta]-mannosidase was amplified by RT-PCR to produce a series of overlapping amplicons. One region did not produce an expected 495 bp product, but instead two shorter PCR products were observed, suggesting aberrant splicing (Fig. 5 A). To elucidate the genomic structure in this region we used human genomic DNA for PCR amplification with primers closely situated on the cDNA sequence (Fig. 6 B). One primer pair was found to produce a larger 750 bp amplicon from the genomic template than from the cDNA template, indicating the presence on an intron. The exon/intron borders of the normal control were identified and compared with the DNA sequence from the affected siblings (Fig. 6 C). An A -> G transition was identified at a 3' splice acceptor site in DNA from both patients.
In this paper we report the full cDNA sequence of human [beta]-mannosidase obtained from cDNA clones, RT-PCR and 5' RACE. The composite cDNA contains 3293 nt, consisting of an 87 nt 5'-UTR, 2640 nt coding region and 566 nt 3'-UTR. Homology of the coding region sequence to goat and bovine [beta]-mannosidase as well as our identification of a mutation in patients with [beta]-mannosidosis verifies the identity of this sequence as human [beta]-mannosidase. The conserved size of the human, caprine and bovine coding regions and the 75% amino acid sequence identity (14 ,29 ) reflect a high degree of evolutionary conservation of the enzyme. The human open reading frame codes for 879 amino acid residues starting with a typical signal peptide sequence (30 ). The deduced human [beta]-mannosidase sequence contains eight potential N-glycosylation sites, in contrast to six and four potential sites predicted for the bovine and caprine proteins respectively (14 ,29 ). Three of these sites are shared between all three species. No consensus of the final processed molecular weight and subunit composition of human [beta]-mannosidase has been reached (31 ,32 ). [beta]-Mannosidase purified from bovine kidney is 100 and 110 kDa (33 ), while the goat kidney enzyme is 90 and 100 kDa (34 ). Deglycosylation of both ruminant enzymes yields two peptides of 91 and 86 kDa in each species (33 ,34 ). The degree of glycosylation of the human enzyme is not known.
The 3'-UTR of the human transcript is shorter than the corresponding region in the bovine mRNA, mainly due to stretches of missing bases. This size difference is consistent with northern analysis, which indicates a 3.7 kb human transcript, compared with 4.2 kb in ruminants (29 ). There is no evidence for multiple human transcripts, although several potential polyadenylation sites are present in the 3'-UTR. The northern analysis also demonstrates that there is differential tissue mRNA expression that is consistent with studies of enzyme activity levels in goat tissues (35 ).
Previous studies by Fisher et al. (28 ) and Chen et al. (29 ) indicated that the gene for [beta]-mannosidase is located on human chromosome 4. We further pinpointed the gene location to 4q21-25 using somatic cell hybrids with deletions of chromosome 4. This is in agreement with the assignment of mouse [beta]-mannosidase to chromosome 3 (36 ), which is homologous to human 4q22-28 (37 ), and of bovine [beta]-mannosidase to chromosome 6q3 (38 ). Homology of synteny between human and mouse chromosomes would suggest that the human chromosomal region containing the [beta]-mannosidase gene could be narrowed to 4q22-25.
A 3' splice site mutation was found to cause [beta]-mannosidosis in this family, with severe but heterogeneous manifestations of the disease (19 ). The affected sister, who died at 20 years from bronchopneumonia, had coarse facies, hypertelorism, macroglossia, gingivial hyperplasia, short neck, umbilical hernia, skeletal abnormalities, severe psychomotor retardation and recurrent skin and respiratory infections. Her older brother was, at 30 years of age, less severely affected, with coarse facies, moderate retardation, hearing impairment and recurrent infections.
The AG -> GG transition in the splice acceptor site is congruent with a previous report that in human genetic diseases mutations of the invariant A at position -2 of the 3' splice acceptor site occur more often than expected based on the dinucleotide mutability (39 ). The length of the pyrimidine tract adjacent to the AG at the 3' splice acceptor site has been implicated in the strength of the effect the mutation has on appropriate splicing (39 ). Although the pyrimidine tract adjacent to the AG in the human [beta]-mannosidase intron is 22 bp long, it was insufficient to alleviate the effect of the mutation.
Splice mutations can result in one or a combination of splicing defects, such as exon skipping, activation of a cryptic splice site or intron retention (40 ). The mutation in this family results in activation of a cryptic site in the exon immediately downstream of the lesion and skipping of the same exon. Either transcript predicts a significantly altered peptide. Cryptic splice activation leads to a truncated protein, while skipping of the entire exon results in an in-frame deletion and predicts a protein lacking 86 internal amino acids. Further studies will be required to assess whether the peptides are expressed in these patients. Low levels of normal mRNA splicing have been encountered with splice site mutations associated with other genetic diseases and can reduce the severity of the disease (41 ). Since the disease phenotype differed between the two siblings, it is possible that a low level of normal splicing may occur in the more mildly affected brother. However, no evidence for normal splicing was observed in either patient's cultured fibroblast mRNA. The mutation test performed by PCR amplification of genomic DNA flanking the mutation site and subsequent SmaI restriction digestion confirms homozygosity for the mutation in the [beta]-mannosidosis patients. The mutation was not found in 186 control chromosomes, demonstrating that this sequence variation is not a polymorphism.
The availability of the human [beta]-mannosidase cDNA sequence will permit studies of the structure and expression of this enzyme. Identification of the mutation will allow us to explore the effect of a large in-frame deletion on expression and activity of human [beta]-mannosidase.
A human placental cDNA library constructed in [lambda]ZapII (Stratagene) was screened according to the manufacturer's suggested protocol with a PCR-derived probe. The probe was obtained by amplification of DNA from the human placental cDNA library [lambda]ZAPII using a 5' sense primer, BH82, derived from a human expressed sequence tag (Genbank accession no. humxt01397) that showed 80% sequence identity to bovine [beta]-mannosidase cDNA, and a 3' antisense primer, BB89, based on the bovine cDNA sequence (29 ). The amplified 775 bp DNA fragment,hu 82/89, was labeled with [[alpha]-32P]dCTP by random primed labeling (Boehringer Mannheim) to a specific activity of 1.15 × 109 d.p.m./µg. A set of 20 nylon filters (NEN Research Products) containing a total of 106 p.f.u. from the human placenta cDNA library was prehybridized in 50% formamide, 6× SSPE, 5× Denhardts, 0.1% SDS and 100 µg/ml denatured herring sperm DNA for 3 h at 42°C. Hybridization was subsequently performed in the same solution by adding the denatured hu 82/89 probe at 106 c.p.m./ml and incubating for 16 h at 42°C. Filters were washed twice with 1× SSC, 0.1% SDS at room temperature and once with 0.5× SSC, 0.1% SDS for 1 h at 42°C. Positive plaques were picked, purified and in vivo excision of the phagemid pBluescript (SK-) was performed according to the Stratagene protocol. Plasmid DNA was purified using a Promega Wizard miniprep kit. Three independent clones were sequenced at Michigan State University and University of Michigan sequencing facilities using an ABI 373A DNA sequencer. Sequence analysis and contig assembly was performed using GCG and Sequencher computer programs.
[beta]-Mannosidase sequence information obtained from the cDNA clones was used to design primers (S & E software) for use in RT-PCR reactions to complete sequencing of the human cDNA. Ten micrograms of human placenta total RNA (Clontech) was reverse transcribed with Mu-MLV-RT (Gibco-BRL) using the 3' antisense primer BH145 to synthesize first strand cDNA. The cDNA was ethanol precipitated and resuspended in 50 µl H2O. PCR reactions were performed using 2 µl from the above reaction as template in a 20 µl final reaction volume containing 1× PCR buffer (Perkin Elmer), 0.2 mM each dNTP, 2 mM MgCl2, 1 µM each primer, 1 U Taq polymerase (Perkin Elmer). PCR conditions were initial denaturation for 7 min at 94°C, followed by 25 cycles of denaturation for 45 s at 94°C, annealing for 45 s at between 55 and 64°C, according to the Tm of the primers, and elongation for 45 s at 72°C, with a final elongation step of 10 min at 72°C. The total number of cycles was kept at 25 per reaction and reactions were performed in triplicate and pooled to avoid Taq-induced errors. The amplified fragments were size fractionated by 0.5× TBE, 1% agarose gel electrophoresis and gel purified using Promega's Wizard PCR Preps DNA purification system. Figure 1 illustrates the relative position of the fragments and the primer pairs that were used to produce them. Table 1 describes the sequence orientation and the nucleotide positions of the primers. All fragments were sequenced in both orientations using PCR primers and internal primers where applicable.
5' Rapid amplification of cDNA ends (RACE) was performed according to the manufacturer's protocol (Gibco-BRL). Gene-specific primers BH120 and BH121 were designed from the composite cDNA sequence of RT-PCR and cDNA clones. BH120 was used to synthesize first strand cDNA. After C tailing, PCR amplification was performed using the antisense nested primer BH121 and an anchor primer provided by the manufacturer using the recommended conditions. Amplified fragments were cloned into pCRII. Plasmid DNA was purified and sequenced as described above.
A human Multiple Tissue Northern Blot (Clontech) was hybridized with radiolabeled probe hu 82/89 using the Clontech protocol. After hybridization to the [beta]-mannosidase-specific probe the same membrane was hybridized to a control [beta]-actin cDNA provided by the manufacturer. Relative gene expression was determined by quantitating the intensities of the [beta]-mannosidase and [beta]-actin specific bands in the northern blot using a phosphorimager (model 400 B; Molecular Dynamics, Sunnyvale, CA).
Using genomic DNA as a template, primer pair BH150 and BH156 was used to PCR amplify a 276 bp product from the 3' coding exon. The annealing temperature for the PCR was raised to 64°C to specifically amplify human genomic DNA isolated from rodent/human cell hybrids (NIGMS Coriell Cell Repositories) in which human chromosomes 1-22, X and Y were retained individually in each cell line. To localize the region of chromosome 4 containing the human [beta]-mannosidase gene, DNA from a second set of hamster/human hybrid cell lines retaining various overlapping deletions of human chromosome 4 was tested (NA10115, NA11447, NA11449, NA13396 and NA13402; HIGMS Human Genetic Mutant Cell Repository, Coriell Cell Repositories).
Fibroblast cultures established from five members of a Czech family (parents, two children affected with [beta]-mannosidosis and a heterozygote sister, all confirmed by enzyme activity levels; 19 ) were grown in F10 medium (Gibco-BRL), 15% FCS and 1× penicillin/streptomycin (Gibco-BRL). RNA was prepared from fibroblast cell cultures using TriZol reagent (Gibco-BRL) and genomic DNA was isolated using a Puregene DNA isolation kit (Gentra). For RT-PCR analysis 5 µg total RNA from the five cell lines and from normal RNA were reverse transcribed using antisense primer BH145. The following primer pairs were used for PCR amplification of the cDNAs: BB118 and BB113; BB96 and BH139; BH137 and BB89; BH150 and BH145. To amplify control and patient genomic DNA primer pair BH137 and BH155 was used under the following PCR conditions: initial denaturation cycle at 94°C for 7 min, 30 cycles of 45 s denaturation, 40 s annealing at 65°C and 60 s extension at 72°C and final extension at 72°C for 10 min. The PCR products from the genomic DNA templates were sequenced and intron/exon borders identified. For the mutation test primer BH160, based on intron sequence, was designed for use in combination with BH155 under similar PCR reaction conditions as above except that 62°C was used as the annealing temperature. Ten microliters of the resultant PCR reaction was digested with 10 U SmaI (Boehringer Mannheim) and subsequently resolved by 1% agarose gel electrophoresis.
The authors thank Dr Margaret Jones for advice, critical reading of the manuscript and support of studies leading to this publication (NS16886). This work was also supported by a Michigan State University All University Research Initiation Grant (KHF), by NIH grant DK49782 (KHF), by an education grant (AHA) from Sultan Qaboos University, Sultanate of Oman and by grant IGA MZ CR no. 1148-6 (MM).
1 Hartley,W.J. and Blakemore,W.F. (1973) Neurovisceral storage and dysmyelinogenesis in neonatal goats. Acta Neuropathol., 25, 325-333.MEDLINE Abstract
2 Jones,M.Z. and Laine,R.A. (1981) Caprine oligosaccharide storage disease: accumulation of [beta]-mannosyl(1-4)[beta]-N-acetylglucosaminyl(1-4)[beta]-N-acetylglucosamine in brain. J. Biol. Chem., 256, 5181-5184.MEDLINE Abstract
3 Healy,P.J., Seaman,J.T., Gardner,I.A. and Sewell,C.A. (1981) [beta]-Mannosidase deficiency in anglo nubian goats. Aust. Vet. J., 57, 504-507.
4 Jones,M.Z. and Dawson,G. (1981) Caprine [beta]-mannosidosis: inherited deficiency of [beta]-mannosidase. J. Biol. Chem., 256, 5185-5188.MEDLINE Abstract
5 Abbitt,B., Jones,M.Z., Kasari,T.R., Storts,R.W., Templeton,J.W., Holland,P. and Castenson,P. (1991) [beta]-Mannosidosis in twelve Salers calves. J. Am. Vet. Med. Ass., 198, 109-113.
7 Jolly,R.D., Thompson,K.G., Bayliss,S.L., Vidler,B.M., Orr,M.B. and Healy,P.L. (1990) [beta]-Mannosidosis in a Salers calf: a new storage disease of cattle. N. Z. Vet. J., 38, 102-105.
8 Jones,M.Z., Cunningham,J.G., Dade,A.W., Alessi,D.M., Mostosky,U.V., Vorro,J.R., Benitez,J.T. and Lovell,K.L. (1983) Caprine [beta]-mannosidosis: clinical and pathological features. J. Neuropathol. Exp. Neurol., 42, 268-285.MEDLINE Abstract
9 Render,J.A., Lovell,K.L. and Keller,C.B. (1992) The ocular and otic pathology of bovine [beta]-mannosidosis. J. Vet. Diagnosis Invest., 4, 96-98.
10 Matsuura,F., Laine,R.A. and Jones,M.Z. (1981) Oligosaccharides accumulated in the kidney of a goat with [beta]-mannosidosis: mass spectrometry of intact permethylated derivatives. Arch. Biochem. Biophys., 211, 485-493.MEDLINE Abstract
11 Jones,M.Z., Rathke,E.J.S., Gage,D.A., Costello,C.E., Murakami,K., Ohta,M. and Matsuura,F. (1992) Oligosaccharides accumulated in the bovine [beta]-mannosidosis kidney. J. Inherited Metab. Dis., 15, 57-67.MEDLINE Abstract
12 Jones,M.Z., Rathke,E.J.S. Cavanagh,K. and Hancock,L.W. (1984) [beta]-Mannosidosis: prenatal biochemical and morphological characteristics. J. Inherited Metab. Dis., 7, 80-85.MEDLINE Abstract
13 Cavanagh,K., Dunstan,R.W. and Jones,M.Z. (1982) Plasma [alpha]- and [beta]-mannosidase activities in caprine [beta]-mannosidosis. Am. J. Vet. Res., 43, 1058-1059.MEDLINE Abstract
14 Leipprandt,J.R., Kraemer,S.A., Haithcock,B.E., Chen,H., Dyme,J.L., Cavanagh,K.T., Friderici,K.H. and Jones,M.Z. (1996) Caprine [beta]-mannosidase: sequencing and characterization of the cDNA and identification of the molecular defect of caprine [beta]-mannosidosis. Genomics, 37, 51-56.MEDLINE Abstract
15 Wenger,D.A., Sujansky,E., Fennessey,P.V. and Thompson,J.N. (1986) Human [beta]-mannosidase deficiency. New Engl. J. Med., 315, 1201-1205.MEDLINE Abstract
16 Cooper,A., Sardharwalla,I.B. and Roberts,M.M. (1986) Human [beta]-mannosidase deficiency. New Engl. J. Med., 315, 1231MEDLINE Abstract
17 Cooper,A., Wraith,J.E., Savage,W.J., Thornley,M. and Noronha,M.J. (1991) [beta]-Mannosidase deficiency in a female infant with epileptic encephalopathy. J. Inherited Metab. Dis., 14, 18-22.MEDLINE Abstract
18 Dorland,L., Duran,M., Hoefnagels,F.E.T., Breg,J.N., Fabery de Jonge,H., van Eeghen-Cransberg,K., Van Sprang,F.J. and van Diggelen,O.P. (1988) [beta]-Mannosidosis in two brothers with hearing loss. J. Inherited Metab. Dis., 11, 255-258.MEDLINE Abstract
19 Kleijer,W.J., Hu,P., Thoomes,R., Boer,M., Huijmans,J.G.M., Blom,W., van Diggelen,O.P., Seemanova,E. and Macek,M. (1990) [beta]-Mannosidase deficiency: heterogeneous manifestations in the first female patient and her brother. J. Inherited Metab. Dis., 13, 867-872.MEDLINE Abstract
20 Poenaru,L., Akli, S., Rocchiccioli, F., Eydoux,P. and Zamet,P. (1992) Human [beta]-mannosidosis: a 3-year-old boy with speech impairment and emotional instability. Clin. Genet., 41, 331-334.MEDLINE Abstract
21 Wijburg,H., De Jong, J., Wevers, R., Bakkeren, J., Trijbels,F. and Sengers,R. (1992) Beta-mannosidosis and ethanolaminuria in a female patient. Eur. J. Pediat., 151, 311
22 Levade,T., Graber, D., Flurin, V., Delisle, M.-B., Pieraggi, M.-T., Testut, M.-F., Carrière,J.-P. and Salvayre,R. (1994) Human [beta]-mannosidase deficiency associated with peripheral neuropathy. Ann. Neurol., 35, 116-119.MEDLINE Abstract
23 Rodriguez-Serna,M., Botella-Estrada, R., Chabas, A., Coll, M., Oliver, V., Febrer,M. and Aliaga,A. (1996) Angiokeratoma corporis diffusum associated with [beta]-mannosidase deficiency. Arch. Dermatol., 132, 1219-1222.MEDLINE Abstract
24 Gourrier,E., Thomas,M. P., Munnich,A., Poenaru,L., Asensi,D., Jan,D. and Leraillez,J. (1997) A new case of beta mannosidosis. Arch. Pediat., 4, 147-151.
25 Cooper,A., Hatton,C., Thornley,M. and Sardharwalla,I.B. (1988) Human [beta]-mannosidase deficiency: biochemical findings in plasma, fibroblasts, white cells and urine. J. Inherited Metab. Dis., 11, 17-29.MEDLINE Abstract
26 Van Pelt,J., Hokke,C.H., Dorland,L., Duran,M., Kamerling,J.P. and Vliegenthart,J.F.G. (1990) Accumulation of mannosyl-[beta] (1 -> 4)-N-acetylglucosamine in fibroblasts and leukocytes of patients with a deficiency of [beta]-mannosidase. Clin. Chim. Acta, 187, 55-60.MEDLINE Abstract
27 Kozak,M. (1987) An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNA. Nucleic Acids Res., 15, 8125-8132.MEDLINE Abstract
28 Fisher,R.A., Povey,S., Cavanagh,K., Dupuis,M. and Jones,M.Z. (1987) Studies to determine the chromosome assignment of human lysosomal [beta]-mannosidase (MANBA). Am. J. Hum. Genet., 41, A165
29 Chen,H., Leipprandt,J.R., Traviss,C.E., Sopher,B.L., Jones,M.Z., Cavanagh,K.T. and Friderici,K.H. (1995) Molecular cloning and characterization of bovine [beta]-mannosidase. J. Biol. Chem., 270, 3841-3848.MEDLINE Abstract
30 von Heijne,G. (1986) A new method for predicting signal sequence cleavage sites. Nucleic Acids Res., 14, 4683-4690.MEDLINE Abstract
31 Iwasaki,Y., Tsuji,A., Omura,K. and Suzuki,Y. (1989) Purification and characterization of [beta]-mannosidase from human placenta. J. Biochem., 106, 331-335.MEDLINE Abstract
32 Guadalupi,R., Bernard,M., Orlacchio,A., Foglietti,M.J. and Emiliani,C. (1996) Purification and properties of human urinary beta-D-mannosidase. Biochem. Biophys. Acta, 1293, 9-16.
33 Sopher,B.L., Traviss,C.E., Cavanagh,K.T., Jones,M.Z. and Friderici,K.H. (1993) Bovine kidney [beta]-mannosidase: purification and characterization. Biochem. J., 289, 343-347.MEDLINE Abstract
34 Sopher,B.L., Traviss,C.E., Cavanagh,K.T., Jones,M.Z. and Friderici,K.H. (1992) Purification and characterization of goat lysosomal [beta]-mannosidase using monoclonal and polyclonal antibodies. J. Biol. Chem., 267, 6178-6182.MEDLINE Abstract
35 Lovell,K.L., Kranich,R. and Cavanagh,K. (1994) Biochemical and histochemical analysis of lysosomal enzyme activities in caprine [beta]-mannosidosis. Mol. Chem. Neuropathol., 21, 61-74.MEDLINE Abstract
36 Lundin,L.-G. (1987) A gene (Bmn) controlling [beta]-mannosidase activity in the mouse is located in the distal part of chromosome 3. Biochem. Genet., 25, 603-610.MEDLINE Abstract
37 O'Brien,S.J., Womack,J.E., Lyons,L.A., Moore,K.J., Jenkins,N.A. and Copeland,N.G. (1993) Anchored reference loci for comparative genome mapping in mammals. Nature Genet., 3, 103-112.MEDLINE Abstract
38 Schmutz,S.M., Moker,J.S., Leipprandt,J.R. and Friderici,K.H. (1996) Beta-mannosidase maps to cattle chromosome 6. Mamm. Genome, 7, 474.MEDLINE Abstract
39 Krawczak,M., Reiss,J. and Cooper,D.N. (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet., 90, 41-54.MEDLINE Abstract
40 Maquat,L.E. (1996) Defects in RNA splicing and the consequence of shortened translational reading frames. Am. J. Hum. Genet., 59, 279-286.MEDLINE Abstract
41 Raben,N., Nichols,R.C., Martiniuk,F. and Plotz,P.H. (1996) A model of mRNA splicing in adult lysosomal storage disease (glycogenosis type II). Hum. Mol. Genet., 5, 995-1000.MEDLINE Abstract
*To whom correspondence should be addressed. Tel: +1 517 353 9160; Fax: +1 517 432 1053; Email: friderici@pathology.cvm.msu.edu
M. Zhu, K. L. Lovell, J. S. Patterson, T. L. Saunders, E. D. Hughes, and K. H. Friderici {beta}-Mannosidosis mice: a model for the human lysosomal storage disease
Hum. Mol. Genet.,
February 1, 2006;
15(3):
493 - 500.
[Abstract][Full Text][PDF]
F. Sedel, K. Friderici, K. Nummy, C. Caillaud, A. Chabli, A. Durr, C. Lubetzki, and Y. Agid Atypical Gilles de la Tourette Syndrome With {beta}-Mannosidase Deficiency
Arch Neurol,
January 1, 2006;
63(1):
129 - 131.
[Abstract][Full Text][PDF]
J. Kralovicova, M. B. Christensen, and I. Vorechovsky Biased exon/intron distribution of cryptic and de novo 3' splice sites
Nucleic Acids Res.,
September 1, 2005;
33(15):
4882 - 4898.
[Abstract][Full Text][PDF]
B. Winchester Lysosomal metabolism of glycoproteins
Glycobiology,
June 1, 2005;
15(6):
1R - 15R.
[Abstract][Full Text][PDF]
A. Sasaki, T. Ishimizu, and S. Hase Substrate Specificity and Molecular Cloning of the Lily Endo-{beta}-Mannosidase Acting on N-Glycan
J. Biochem.,
January 1, 2005;
137(1):
87 - 93.
[Abstract][Full Text][PDF]
T. Ishimizu, A. Sasaki, S. Okutani, M. Maeda, M. Yamagishi, and S. Hase Endo-{beta}-mannosidase, a Plant Enzyme Acting on N-Glycan: PURIFICATION, MOLECULAR CLONING, AND CHARACTERIZATION
J. Biol. Chem.,
September 10, 2004;
279(37):
38555 - 38562.
[Abstract][Full Text][PDF]
E. Beki, I. Nagy, J. Vanderleyden, S. Jager, L. Kiss, L. Fulop, L. Hornok, and J. Kukolya Cloning and Heterologous Expression of a {beta}-D-Mannosidase (EC 3.2.1.25)-Encoding Gene from Thermobifida fusca TM51
Appl. Envir. Microbiol.,
April 1, 2003;
69(4):
1944 - 1952.
[Abstract][Full Text][PDF]
P. Durand, S. Fabrega, B. Henrissat, J.-P. Mornon, and P. Lehn Structural features of normal and mutant human lysosomal glycoside hydrolases deduced from bioinformatics analysis
Hum. Mol. Genet.,
April 1, 2000;
9(6):
967 - 977.
[Abstract][Full Text][PDF]
D. Stoll, H. Stålbrand, and R. A. J. Warren Mannan-Degrading Enzymes from Cellulomonas fimi
Appl. Envir. Microbiol.,
June 1, 1999;
65(6):
2598 - 2605.
[Abstract][Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
