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M Z Jones

Publications and source records attributed to M Z Jones.

At least 19 recordsLinked to original sources
PubMed2001

Metabolic studies of glycosphingolipid accumulation in mucopolysaccharidosis IIID.

Severe neurological deficits and mental retardation are frequently associated with disrupted ganglioside metabolism in a variety of gangliosidoses and lysosomal storage disorders. Accumulation of glycosphingolipids (GSLs) in the central nervous system (CNS) of humans and animals affected with several types of mucopolysaccharidoses (MPS) also correlates with the severity of neurological dysfunction. Mucopolysaccharidosis type IIID (MPS IIID) is characterized by deficiency in lysosomal N-acetylglucosamine 6-sulfatase activity and the accumulation and excretion of heparan sulfates and N-acetylglucosamine 6-sulfate. We investigated the metabolism of GSLs in the prenatal, neonatal, and adult MPS IIID caprine brains and an MPS experimental cell culture model. The amounts of total glycolipids in prenatal, neonatal, and adult MPS IIID caprine brains were about 2-fold higher than those in control samples. GM3, GD3, and lactosyl ceramide were the principal GSLs which abnormally accumulated in caprine MPS IIID brains. These changes may be, in part, due to the reduction of sialidase and UDP-N-acetylgalactosamine:GM3 N-acetylgalactosaminyltransferase (GalNAc-T) activities in MPS IIID caprine brain. To further examine the possible mechanism of GSL accumulation in MPS IIID brains, we employed a cell culture model using suramin-treated neuronal cultures of differentiated P19 cells. HPTLC analysis showed elevated GSLs in suramin-treated cells. Metabolic pulse-chase labeling study revealed that the GSL accumulation in suramin-treated cells may be attributed to both disturbed biosynthesis and significantly slower degradation of GSLs. In addition, the consistency of observations in the cell culture and caprine models supports the cell culture system as a means of evaluating GSL metabolic perturbations.

Age Factors↗
PubMed2000

Caprine mucopolysaccharidosis IIID: a preliminary trial of enzyme replacement therapy.

Mucopolysaccharidosis type IIID (MPS IIID) is a lysosomal storage disorder resulting from lack of activity of the lysosomal hydrolase N-acetylglucosamine 6-sulfatase (6S) (EC 3.1.6.14). The syndrome is associated with systemic and central nervous system (CNS) heparan sulfate glycosaminoglycan (HS-GAG) accumulation, secondary storage of lipids, and severe, progressive dementia. In this investigation, caprine MPS IIID, established as a large animal model for the human disease, was used to evaluate the efficacy of enzyme replacement therapy (ERT). Recombinant caprine 6S (rc6S) (1 mg/kg/dose) was administered intravenously to one MPS IIID goat kid at 2, 3, and 4 wks of age. Five days after the last dose, the uronic acid (UA) content and the composition of uncatabolized HS-GAG fractions in the brain of the ERT-treated MPS IIID kid were similar to those from a control, untreated MPS IIID animal. However, hepatic uronic acid levels in the treated MPS IIID kid were approximately 90% lower than those in the untreated MPS IIID control; whereas the composition of the residual hepatic HS-GAG was identical to that in the untreated animal. Marked reduction of lysosomal storage vacuoles in hepatic cells of the treated MPS IIID kid was observed, but ERT had no effect on CNS lesions. No residual 6S activity was detected in brain or liver. This preliminary investigation indicates that other treatment regimens will be necessary to ameliorate MPS III-related CNS lesions.

Animals↗
PubMed1999

Identification of a bovine beta-mannosidosis mutation and detection of two beta-mannosidase pseudogenes.

Beta-mannosidase deficiency results in beta-mannosidosis, a severe neurodegenerative lysosomal storage disease identified in cattle, goats, and humans. To more fully understand the molecular pathology of this disease, the mutation associated with bovine beta-mannosidosis was identified by sequence analysis of cDNA from an affected calf. A transition mutation of G to A at position 2574 of the cDNA coding sequence creates a premature stop codon near the 3' end of the protein coding region. To aid commercial breeders of Salers cattle, a PCR-based test was developed to detect the mutation for beta-mannosidosis carrier screening. Application of this test also revealed the presence of two beta-mannosidase pseudogenes. Portions of the pseudogenes were amplified with allele-specific primers and then sequenced. One pseudogene was highly homologous (>99% sequence identity) to the expressed cDNA sequence over the 1292 bp that were sequenced, while the other showed more divergence (83% sequence identity) in the 477 bp that were sequenced. Both are processed pseudogenes that are not expressed. The severity of the bovine beta-mannosidosis phenotype suggests that the 22 C-terminal amino acids of beta-mannosidase play an important role in the function of this enzyme.

Animals↗
PubMed1999

Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains.

To evaluate whether in vivo accumulations of heparan sulfate caused by inborn errors in the metabolism of glycosaminoglycans lead to the formation of neurofibrillary tangles and/or senile plaques, as seen in Alzheimer disease (AD), we studied postmortem brains from 9 patients, ages 1 to 42 years, with mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndrome (MPS I: n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as from caprine MPS IIID and murine MPS VII models were evaluated by thioflavine-S staining and by immunohistochemistry using antibodies directed against heparan sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A beta [1-42]). A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was also utilized to compare levels of total soluble and insoluble A beta (1-40) and A beta (1-42) obtained from temporal cortex of MPS patients. Although no neurofibrillary tangles, senile plaques, or tau-positive lesions were detected in any of the MPS brains studied here, antibodies directed against A beta (1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains of the MPS patients and the caprine MPS model. The ELISA assay also demonstrated a significant 3-fold increase in the level of soluble A beta (1-40) in the MPS brains compared with normal control brains. Thus, at least some of the metabolic defects that lead to accumulations of glycosaminoglycans in MPS also are associated with an increase in immunoreactive A beta (1-40) within the cytoplasmic compartment where they could contribute to the dysfunction and death of affected cells in these disorders, but not induce the formation of plaques and tangles. Models of MPS may enable mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.

Adolescent↗
PubMed1999

Alpha-mannosidosis in the guinea pig: a new animal model for lysosomal storage disorders.

Alpha-mannosidosis is a lysosomal storage disorder resulting from deficient activity of lysosomal alpha-mannosidase. It has been described previously in humans, cattle, and cats, and is characterized in all of these species principally by neuronal storage leading to progressive mental deterioration. Two guinea pigs with stunted growth, progressive mental dullness, behavioral abnormalities, and abnormal posture and gait, showed a deficiency of acidic alpha-mannosidase activity in leukocytes, plasma, fibroblasts, and whole liver extracts. Fractionation of liver demonstrated a deficiency of lysosomal (acidic) alpha-mannosidase activity. Thin layer chromatography of urine and tissue extracts confirmed the diagnosis by demonstrating a pattern of excreted and stored oligosaccharides almost identical to that of urine from a human alpha-mannosidosis patient. Widespread neuronal vacuolation was observed throughout the CNS, including the cerebral cortex, hippocampus, thalamus, cerebellum, midbrain, pons, medulla, and the dorsal and ventral horns of the spinal cord. Lysosomal vacuolation also occurred in many other visceral tissues and was particularly severe in pancreas, thyroid, epididymis, and peripheral ganglion. Axonal spheroids were observed in some brain regions, but gliosis and demyelination were not observed. Ultrastructurally, most vacuoles in both the CNS and visceral tissues were lucent or contained fine fibrillar or flocculent material. Rare large neurons in the cerebral cortex contained fine membranous structures. Skeletal abnormalities were very mild. Alpha-mannosidosis in the guinea pig closely resembles the human disease and will provide a convenient model for investigation of new therapeutic strategies for neuronal storage diseases, such as enzyme replacement and gene replacement therapies.

Animals↗
PubMed1999

Amylopectinosis in fetal and neonatal Quarter Horses.

Three Quarter Horses, a stillborn filly (horse No. 1), a female fetus aborted at approximately 6 months of gestation (horse No. 2), and a 1-month-old colt that had been weak at birth (horse No. 3), had myopathy characterized histologically by large spherical or ovoid inclusions in skeletal and cardiac myofibers. Smaller inclusions were also found in brain and spinal cord and in some cells of all other tissues examined. These inclusions were basophilic, red-purple after staining with periodic acid-Schiff (both before and after digestion with diastase), and moderately dark blue after staining with toluidine blue. The inclusions did not react when stained with Congo red. Staining with iodine ranged from pale blue to black. Their ultrastructural appearance varied from amorphous to somewhat filamentous. On the basis of staining characteristics and diastase resistance, we concluded that these inclusions contained amylopectin. A distinctly different kind of inclusion material was also present in skeletal muscle and tongue of horse Nos. 1 and 3. These inclusions were crystalline with a sharply defined ultrastructural periodicity. The crystals were eosinophilic and very dark blue when stained with toluidine blue but did not stain with iodine. Crystals sometimes occurred freely within the myofibers but more often were encased by deposits of amylopectin. This combination of histologic and ultrastructural features characterizes a previously unreported storage disease in fetal and neonatal Quarter Horses, with findings similar to those of glycogen storage disease type IV. We speculate that a severe inherited loss of glycogen brancher enzyme activity may be responsible for these findings. The relation of amylopectinosis to the death of the foals is unknown.

Amylopectin↗
PubMed1998

Caprine mucopolysaccharidosis-IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Several animal models have been developed for the mucopolysaccharidoses (MPSs), a group of lysosomal storage disorders caused by lysosomal hydrolase deficiencies that disrupt the catabolism of glycosaminoglycans (GAG). Among the MPS, the MPS-III (Sanfilippo) syndromes lacked an animal counterpart until recently. In this investigation of caprine MPS-IIID, the clinical, biochemical, morphological, and immunohistochemical studies revealed severe and mild phenotypes like those observed in human MPS III syndromes. Both forms of caprine MPS IIID result from a nonsense mutation and consequent deficiency of lysosomal N-acetylglucosamine 6-sulfatase (G6S) activity and are associated with tissue storage and urinary excretion of heparan sulfate (HS). Using special stains, immunohistochemistry, and electron microscopy, secondary lysosomes filled with GAG were identified in most tissues from affected goats. Primary neuronal accumulation of HS and the secondary storage of gangliosides were observed in the central nervous system (CNS) of these animals. In addition, morphological changes in the CNS such as neuritic expansions and other neuronal alterations that may have functional significance were also seen. The spectrum of lesions was greater in the severe form of caprine MPS IIID and included mild cartilaginous, bony, and corneal lesions. The more pronounced neurological deficits in the severe form were partly related to a greater extent of CNS dysmyelination. These findings demonstrate that caprine MPS IIID is a suitable animal model for the investigation of therapeutic strategies for MPS III syndromes.

Animals↗
PubMed1998

Recombinant caprine 3H-[N-acetylglucosamine-6-sulfatase] and human 3H-[N-acetylgalactosamine-4-sulfatase]: plasma clearance, tissue distribution, and cellular uptake in the rat.

The use of recombinant lysosomal enzymes for enzyme replacement therapy (ERT) is likely to be a necessary component of effective treatment regimens for lysosomal storage diseases (LSDs). The mechanism and rate of uptake into target cells, rate of disappearance of the enzyme from plasma, and its tissue distribution are important factors to assess the need for possible modifications to the enzyme, particularly for LSDs that affect the central nervous system (CNS). Two recombinant lysosomal enzymes, caprine N-acetylglucosamine-6-sulfatase (rc6S) and human N-acetylgalactosamine-4-sulfatase (rh4S), deficient in MPS IIID and MPS VI, respectively, were radiolabeled and purified. The major portion (>77%) of each recombinant enzyme contained the mannose-6-phosphate (M6P) recognition marker as demonstrated by their ability to bind to a M6P receptor affinity column. The uptake of 3H-rc6S and 3H-rh4S into cultured rat brain cells was also inhibited by the addition of 5 mM M6P to the culture medium. After iv administration of 0.4-0.5 mg/kg of 3H-rc6S and 1 mg/kg of 3H-rh4S to the rat, both enzymes were rapidly lost from the circulation in a biphasic fashion (t1/2 for 3H-rc6S = 1.25+/-0.15 min and 37.17+/-23.29 min; t1/2 for 3H-rh4S = 0.41 and 5.3 min). At this dose, about 6% of 3H-rc6S, but only 0.49% of 3H-rh4S, remained in the plasma 4 h after administration, whereas approx 30% of 3H-rc6S and more than 50% of 3H-rh4S was found in the liver. At doses of 1.6-2.0 mg/kg of 3H-rc6S and 1 mg/kg 3H-rh4S, but not at the lower dose of 3H-rc6S, trace levels of both 3H-rc6S and 3H-rh4S were detected in the brain. The low level of enzyme recovered from the brain suggests that modification of rc6S will be necessary to achieve sufficient enzyme uptake into the CNS for effective therapy of MPS IIID.

Animals↗
PubMed1997

Expression, purification and characterization of recombinant caprine N-acetylglucosamine-6-sulphatase.

Mucopolysaccharidosis type IIID or Sanfilippo D syndrome is a lysosomal storage disorder caused by the deficiency of N-acetylglucosamine-6-sulphatase (Glc6S). In addition to human patients, a Nubian goat with this disorder has been described and the caprine Glc6S (cGlc6S) cDNA cloned. In this study, the full-length cGlc6S cDNA was inserted into the expression vector, pEFNeo, which placed the cGlc6S cDNA under the transcriptional control of the human polypeptide chain elongation factor promoter. The pEFNeo expression vector also contains the human growth hormone polyadenylation signal and the genes encoding resistance to ampicillin and G418. The cGlc6S expression construct was electroporated into Chinese hamster ovary (CHO-K1) cells, and stably transfected clones were isolated. One clone, CHOrcGlc6S.17, which secreted the highest Glc6S activity into the culture medium, was selected and cultured in cell factories. The secreted recombinant cGlc6S (rcGlc6S) precursor was purified to homogeneity from conditioned medium by a two-column procedure which consisted of a Cu2+-chelating Sepharose column followed by TSK G3000SW gel filtration. The native molecular mass of rcFlc6S was estimated to be 102 kDa and the subunit size was 94 kDa. The kinetic properties of cGlc6S were similar to those of human Glc6S isolated from liver. rcGlc6S was endocytosed by fibroblasts from patients with mucopolysaccharidosis type IIID via the mannose 6-phosphate receptor-mediated pathway resulting in correction of the storage phenotype of these cells.

Animals↗
PubMed1997

Biochemical and morphological expression of early prenatal caprine beta-mannosidosis.

Lysosomal storage diseases associated with early-onset pathological changes may require prenatal therapy to avert the profound effects of the metabolic error on organs, especially the central nervous system. The present investigation determined the extent of expression of beta-mannosidase deficiency in the caprine fetus at 62 days of gestation, near the end of the period of immunotolerance when donor cells can engraft in various organs without immune rejection and supply missing enzyme. Three pairs of obligate carrier goats from the beta-mannosidosis colony were mated. Out of six fetuses delivered at 62 days of gestation, one (V385) was identified by measurement of beta-mannosidase activity as the only fetus affected with beta-mannosidosis. Thin-layer chromatography and quantitation of oligosaccharides revealed the presence of tri- and disaccharides, typical of beta-mannosidosis, only in V385. Morphological analysis revealed cytoplasmic vacuolation typical of beta-mannosidosis in V385; in thyroid, spinal cord, and kidney, the pattern of vacuolation was similar to, but less severe than, that observed previously in newborn affected goats. On the basis of these results, it will be possible to determine the effects of prenatal cell transplantation therapeutic strategies performed during the period of immunotolerance by monitoring phenotypic characteristics after treatment.

Animals↗
PubMed1997

Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants.

We held an international consensus conference on frontotemporal dementia, behavioral disturbances, and parkinsonism linked to chromosome 17 to determine whether these are homogeneous or heterogeneous disorders, to agree on terminology, and to develop strategies for further research. The group identified 13 kindreds with sufficient evidence for linkage, finding in common to all a critical 2 cM between markers D17S791 and D17S800. There was agreement that (1) despite previous descriptions that have emphasized one or another clinical or neuropathological feature, the kindreds share clinical and neuropathological features; (2) until more specific information about the genetic defects becomes available, this disorder is best termed frontotemporal dementia and parkinsonism linked to chromosome 17; and (3) further research will be enhanced by identifying the gene or genes responsible for this disorder, detecting additional cases within known families and, in new families, correlating mutations with phenotypes and more fully delineating the clinical, neuropsychological, and neuropathological characteristics of this disorder.

Brain↗
PubMed1997

The ultrastructure of skin from a patient with mucopolysaccharidosis IIID.

Mucopolysaccharidosis IIID (MPS-IIID) is the rarest of the MPS-III syndromes. It is caused by deficient activity of lysosomal N-acetylglucosamine-6-sulfatase (G6S). To date, the clinical and biochemical features of seven patients with MPS-IIID have been reported, but no biopsy or autopsy findings have been described. The purpose of this report is to define the ultrastructure of affected cells seen in a skin biopsy from a 14-year-old boy. The child presented with progressive mental deterioration, hyperactivity and mild to moderate dysmorphism. The diagnosis of a mucopolysaccharidosis was suggested, but the initial urine analyses were negative for elevated mucopolysaccharides, and only the third analysis showed abnormal excretion of heparan sulfate. Because of the diagnostic difficulties posed by this case, a skin biopsy was performed for morphological and biochemical studies. Numerous vacuoles were noted in Schwann cells, fibroblasts, smooth muscle cells, eccrine gland and ductal epithelium in resin-embedded sections stained with toluidine blue. Ultrastructurally, many lysosomes were distended with abundant, fibrillar material. Occasionally, lamellated membranous structures were present within the same lysosomes. These findings are consistent with those seen in other forms of MPS, in which the lysosomal storage occurs predominantly, but not exclusively, in mesenchymal cells. Furthermore, deficient activity of G6S was confirmed in cultured skin fibroblasts. This study demonstrates that electron microscopy of skin biopsies is a useful method for identification of patients with clinical features of MPS-IIID whether or not heparan sulfaturia is present.

Adolescent↗
PubMed1997

Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Mucopolysaccharidosis IIID (MPS IIID) is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of 10 patients have been reported, the deficient N-acetylglucosamine 6-sulfatase (G6S) enzyme has been purified, and the G6S gene has been cloned, sequenced and localized. However, morphological manifestations of this condition have not been reported and the pathogenesis of the severe neurological deficits remains an enigma. In this paper we describe and correlate the clinical, biochemical and pathological observations for 2 cases of MPS IIID. We used monoclonal antibodies against heparan sulfate (HS) and GM2-ganglioside, thin layer chromatography, mass spectrometry, and morphological techniques to demonstrate the nature and the distribution of the uncatabolized substrates. The majority of the cells in various tissues showed morphological changes expected with lysosomal storage of HS. The central nervous system (CNS) was most severely affected because of the secondary storage of GM2 and GM3 gangliosides in addition to the primary accumulation of HS. The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes. This study supports the hypothesis that the neurological dysfunction and neurodegeneration common to the Sanfilippo syndromes is, in part, due to the secondary metabolic perturbations induced by HS accumulation.

Adolescent↗
PubMed1996

Caprine beta-mannosidase: sequencing and characterization of the cDNA and identification of the molecular defect of caprine beta-mannosidosis.

The complete sequence of the caprine beta-mannosidase cDNA coding region has been determined, and a mutation that is associated with caprine beta-mannosidosis has been identified. Reverse transcriptase-polymerase chain reactions were performed using primers based on bovine and, later, goat cDNA sequences to produce an overlapping series of amplicons covering the entire coding region. The composite cDNA codes for an 879-amino-acid peptide that has four potential N-glycosylation sites. Comparison of the caprine and bovine cDNAs reveals that 96.3% of the nucleotides and 95.2% of the deduced amino acids are identical. A single-base deletion at position 1398 of the coding sequence was identified in the cDNA isolated from a goat affected with beta-mannosidosis. This deletion results in a shift in the reading frame and a premature termination of translation, yielding a deduced peptide of 481 amino acids. An assay, developed to determine the presence or absence of this mutation, confirmed that animals affected with beta-mannosidosis were homozygous for the mutation and that obligate carriers in a caprine beta-mannosidosis colony were heterozygous. This assay accurately distinguished between mutation carrier and noncarrier goats and was used for prenatal diagnosis using DNA collected from fetal fluids. The assay also confirmed chimerism in a goat with an atypically mild beta-mannosidosis phenotype. Thus, this application enables assessment of the efficacy of engraftment of hematopoietic stem cells after prenatal transfer from donor sources.

Amino Acid Sequence↗
PubMed1996

Churg-Strauss syndrome.

The neurologic manifestations of systemic necrotizing vasculitis are heterogeneous and often complex. Late onset asthma, systemic vasculitis manifest by mononeuritis multiplex, and peripheral eosinophilia-the triad of which is consistent with Churg-Strauss syndrome-developed in a 59-year-old woman. Electromyography and nerve conduction studies showed both myelinating and axonal neuropathy involving multiple nerves. Muscle and nerve biopsy showed neurogenic atrophy, demyelination, and axonal changes involving the sural nerve and inflammatory necrotizing small and medium vessel arterial changes. The patient was treated with high-dose prednisone and improved rapidly. Unusual in this case was the lack of multisystemic involvement. Churg-Strauss syndrome is a disease that is being recognized with increased clinical frequency and responds quickly to methylprednisolone treatment.

Churg-Strauss Syndrome↗
PubMed1995

Cloning and sequence analysis of caprine N-acetylglucosamine 6-sulfatase cDNA.

Mucopolysaccharidosis IIID results from the deficiency of N-acetylglucosamine 6-sulfatase activity. A Nubian goat with this lysosomal storage disease has been identified. As a first step in developing this animal model for testing treatment methods, we cloned and sequenced the caprine N-acetylglucosamine 6-sulfatase cDNA coding region. Overall there is 88% nucleotide homology between the goat and human sequence and 94% homology of the deduced amino acid sequence. The human and two ruminant species differ by the presence of an imperfect trinucleotide (CCG) repeat in the ruminant signal sequence.

Amino Acid Sequence↗
PubMed1995

Molecular cloning and characterization of bovine beta-mannosidase.

Deficiency of lysosomal beta-mannosidase activity results in a severe neurodegenerative disease in goats and cattle and a relatively milder phenotype in humans. A cDNA coding for the entire beta-mannosidase protein is described. Mixed oligonucleotides derived from bovine beta-mannosidase peptide sequences were used to screen a bovine thyroid cDNA library. Clones covering about 80% of the C-terminal region were recovered. The missing 5'-region was obtained using the technique of 5'-rapid amplification of cDNA ends. The composite cDNA contains 3852 nucleotides, encoding 879 amino acids. The N-terminal methionine is followed by 16 amino acids displaying the characteristics of a typical signal peptide sequence. The deduced amino acid sequence is colinear with all peptide sequences determined by protein microsequencing. Northern blot analysis demonstrates a single 4.2-kilobase transcript in various tissues from both normal and affected goats and calves. The mRNA level is decreased in tissues of affected beta-mannosidosis animals. The gene encoding beta-mannosidase is localized to human chromosome 4 as shown by Southern analysis of rodent/human somatic cell hybrids. This is the first report of cloning of lysosomal beta-mannosidase.

Amino Acid Sequence↗