Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sandhoff disease is an autosomal recessive lysosomal storage disease resulting from mutations of the HEXB gene encoding the beta subunit of beta-hexosaminidase A. Fibroblast lines from four patients with the infantile form of the disease were investigated for mutations by single strand conformation polymorphism analysis and direct sequencing of PCR products. Two of the cell lines were homozygous for a common, 16 kb deletion of the 5' end of HEXB gene. The two other cell lines contained the 16 kb deletion along with a second mutant allele generating a stop codon: in one case a nonsense mutation, C850-->T, which generated a stop codon at codon 284; and in the other, a single base deletion, delta T1344, which generated a stop codon at codon 451. One additional cell line investigated was a compound heterozygote for two frameshift mutations, delta G774 in exon 7 and delta AG1305-1306 in exon 11 (McInnes et al. 1992, Biochim. Biophys. Acta 1138: 315-317). Stop codons were generated in this cell line at codons 274 and 454, respectively. We took advantage of these genotypes to investigate the steady-state level of mRNA produced by cells containing stop codons using a competitive polymerase chain reaction technique. The mRNA levels were, as percent of normal per single gene dose: for the stop codon at codon 451, 30%; for those at codons 274 and 454, combined percentage of 1.7%; and at codon 284, 0.8%. These studies demonstrate a dramatic difference in the steady-state level of Hex beta mRNA in the cell lines with stop codons in close proximity to each other (codons 451 vs 454).(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1994 Jan
PMID:Impact of premature stop codons on mRNA levels in infantile Sandhoff disease. 816 15

Fucosidosis is an autosomal recessive lysosomal storage disease resulting from absence of alpha-L-fucosidase activity. Lymphoid cell lines from two siblings with fucosidosis and a healthy individual (control) had alpha-L-fucosidase mRNA of normal size (2.3 kb) but the level of alpha-L-fucosidase mRNA in the patients' cells was reduced. cDNA was prepared and amplified from alpha-L-fucosidase mRNA of lymphoid cells of the patients, their carrier parents, and the control. Direct DNA sequencing demonstrated three mutations in the fucosidosis family. One mutation, C1282-->T, changed the codon (CAA) for Gln-422 to a stop codon (UAA). This mutation was heterozygous (C and T) in the patients and their father and independently confirms an earlier report (J. Mol. Neurosci. (1989) 1, 177). Another mutation, C247-->T, changed the codon (CAG) for Gln-77 to a stop codon (UAG) and was heterozygous (C and T) in the patients and their mother. The third mutation, A860-->G, changed the codon CAG for Gln-281 to the codon (CGG) for Arg and was heterozygous (A and G) in the patients but homozygous in their father. alpha-L-Fucosidase activity in cells of the father was 37% of controls indicating that homozygosity of the A860-->G mutation did not cause an absence of alpha-L-fucosidase activity and fucosidosis. This mutation probably results in a normal polymorphic variant of alpha-L-fucosidase. It is proposed that the combination of the C247-->T mutation on the maternal allele of the alpha-L-fucosidase gene and the C1282-->T mutation on the paternal allele caused fucosidosis in the patients.
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PMID:Pedigree analysis of alpha-L-fucosidase gene mutations in a fucosidosis family. 839 58

The rare lysosomal storage disease, fucosidosis results from an almost complete deficiency of alpha-L-fucosidase (EC 3.2.1.51). We have identified six new potential disease causing mutations detected by PCR amplification and sequencing of all 8 exons of the alpha-L-fucosidase gene FUCA1. (1) A C to T mutation (Q77X) in exon 1 of two Jewish-Italian siblings. This mutation was present in one allele and was found also in the mother who was of Italian origin. (2) A C to A mutation (W382X) in exon 6 in an Italian patient. This mutation was found in one allele and obliterates a unique Hphl site. (3) A C to A mutation (Y211X) in exon 3 in a Belgian patient. This mutation obliterates a unique Rsal site and was present in both alleles. (4) A homozygous single base (C) deletion in exon 2 in an Italian patient. This deletion results in a frameshift mutation (P141fs) and obliterates a unique Eael site. (5) A homozygous single base (C) deletion in exon 5 in a Portuguese patient, which also results in a frameshift mutation (S265fs). (6) A single base (A) deletion in exon 3 in a Canadian-Indian patient, which also results in a frameshift mutation (S216fs). The S216fs mutation was found in only one allele; the mutation in the other allele is not yet known.
Hum Mol Genet 1993 Aug
PMID:Six additional mutations in fucosidosis: three nonsense mutations and three frameshift mutations. 840 3

Fucosidosis is a rare lysosomal storage disease due to a nearly complete deficiency of alpha-L-fucosidase (EC 3.2.1.51). In this study, all 8 exons of the alpha-L-fucosidase structural gene (FUCA-1) were amplified by PCR methods, and the amplified products were subcloned and sequenced. Five patient groups with fucosidosis were selected according to their ethnic backgrounds and haplotypes for RFLPs in FUCA-1. Four presumptive disease causing mutations were detected: 1) A major deletion of DNA containing the last two exons of FUCA-1 in two Algerian siblings. 2) A G to T mutation in exon 6 resulting in an in-frame termination codon (E375X) in eight Hispanic patients from Colorado and New Mexico. 3) A G to A mutation (G60D) in exon 1 in four Italian patients and in three related French-American (Cajun) patients. This G60D mutation creates a unique site for AflIII. 4) A frameshift mutation resulted from a two-base deletion in exon 2 (K151fs) in an Italian patient. This deletion obliterates a unique BstXI site and creates a new BpmI site, and was found in only this patient and in only one allele. The rationale for proposing these defects as disease causing mutations includes pedigree analysis and the predicted consequences of each defect upon the activity and the concentration of the enzyme. An A to G transition (Q281R) in exon 5 was found to be present in homozygous form in affected patients and also in normal subjects; it appears to be a newly identified polymorphism. It causes a charge change and may be responsible for the electrophoretic variant phenotype of fucosidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1993 Apr
PMID:Fucosidosis: four new mutations and a new polymorphism. 850 3

Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of aspartylglucosaminidase (AGA). We report here a T214C mutation leading to a Ser72Pro substitution in four Arab families. This is the first naturally occurring AGU mutation involving an active-site amino acid of this recently crystallized hydrolase and it seems to represent the second most common AGU mutation worldwide. The intracellular consequences of the Ser72Pro mutation were analyzed by transient expression in COS-1 cells and we were able to demonstrate that this active-site mutation most probably does not destroy the enzyme activity per se, but specifically prevents the proteolytic activation cleavage of AGA in the endoplasmic reticulum (ER). The mutant enzyme is, however, folded correctly enough to allow mannose-6-phosphorylation and targeting to lysosomes. The overexpressed mutant enzyme remained inactive intracellularly, but the secreted mutant precursor was proteolytically activated extracellularly, resulting in a similar subunit composition to that in the wild-type AGA in the ER. The partially activated mutant enzyme was endocytosed further by the recipient cells. These data demonstrate that the proteolytic activation of AGA can also occur extracellularly and suggest that the driving mechanism of AGA precursor cleavage is autocatalytic.
Hum Mol Genet 1996 Jun
PMID:Ser72Pro active-site disease mutation in human lysosomal aspartylglucosaminidase: abnormal intracellular processing and evidence for extracellular activation. 877 87

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.
Hum Mol Genet 1998 Jan
PMID:Human beta-mannosidase cDNA characterization and first identification of a mutation associated with human beta-mannosidosis. 938 6

Aspartyglucosaminuria (AGU) is a lysosomal storage disease with autosomal recessive inheritance that is caused by deficient activity of aspartylglucosaminidase (AGA), a lysosomal enzyme belonging to the newly described enzyme family of N-terminal hydrolases. An AGU mouse model was generated by targeted disruption of the AGA gene designed to mimic closely one human disease mutation. These homozygous mutant mice have no detectable AGA activity and excrete aspartylglucosamine in their urine. Analogously to the human disease, the affected homozygous animals showed storage in lysosomes in all analyzed tissues, including the brain, liver, kidney and skin, and lysosomal storage was already detected in fetuses at 19 days gestation. Electron microscopic studies of brain tissue samples demonstrated lysosomal storage vacuoles in the neurons and glia of the neocortical and cortical regions. Magnetic resonance images (MRI) facilitating monitoring of the brains of living animals indicated cerebral atrophy and hypointensity of the deep gray matter structures of brain-findings similar to those observed in human patients. AGU mice are fertile, and up to 11 months of age their movement and behavior do not differ from their age-matched littermates. However, in the Morris water maze test, a slow worsening of performance could be seen with age. The phenotype mimics well AGU in humans, the patients characteristically showing only slowly progressive mental retardation and relatively mild skeletal abnormalities.
Hum Mol Genet 1998 Feb
PMID:Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients. 942 33

Scanning methodologies are used for the identification of DNA fragments that differ from the normal nucleotide sequence. Fragments that produce abnormal band patterns are sequenced for characterization of the exact mutation. Factors considered in choosing a scanning methodology include reproducibility, sensitivity, and time. In the present study, we compared single-stranded conformational polymorphism (SSCP) and Cleavase fragment length polymorphism (CFLP) methodologies for mutation scanning of exon VIII in the iduronate 2-sulfatase (IDS) gene. Mutations of the IDS gene result in an X-linked lysosomal storage disease, Hunter syndrome. These six known mutations analyzed by the two methods included a one base pair deletion, a one base pair insertion, and four point mutations. SSCP analysis detected all of the mutations and CFLP analysis detected three of the six mutations. We concluded that SSCP analysis was preferable to CFLP analysis for scanning exon VIII in the IDS gene for mutations.
Biochem Mol Biol Int 1997 Dec
PMID:Comparison of SSCP analysis and CFLP analysis for mutation detection in the human iduronate 2-sulfatase gene. 944 13

Nephropathic cystinosis, an autosomal recessively inherited lysosomal storage disease, results from impaired transport of the disulfide amino acid cystine out of cellular lysosomes. The consequent accumulation and crystallization of cystine destroys tissues, causing growth retardation in infancy, renal failure at 10 years of age, and a variety of other complications. Early oral therapy with the cystine-depleting agent cysteamine prevents renal deterioration and enhances growth. Although the lysosomal cystine carrier has been extensively studied, its molecular structure remains unknown. The lysosomal cystine transporter gene has been mapped by linkage analysis to human chromosome 17p between polymorphic microsatellite markers D17S1583 and D17S1584. Pertinent recombination events and homozygosity by descent has verified that the cystinosis gene lies in the 3.6 cM genetic interval between these two markers. The cystinosis region has been substantially reduced in size by the observation of recombination events in cystinosis patients between markers D17S1828 and D17S2167. According to radiation hybrid analysis, these two markers are separated by 10.2 cR8000 (centirad using 8000 rad radiation hybrids). Estimates of the physical size of this interval range from 187 to 510 kb. Four yeast artificial chromosomes have been identified which form a contig covering the original cystinosis region. Two P1 clones together may span the new, smaller interval, meaning that the cystinosis gene would lie on one of them. Current efforts are being directed toward using these P1 clones to isolate candidate cDNAs by a variety of methods. The ultimate cloning of the cystinosis gene will reveal how functional lysosomal porters are synthesized, targeted, processed, and integrated into the lysosomal membrane.
J Mol Med (Berl) 1998 Apr
PMID:Clinical and molecular aspects of nephropathic cystinosis. 958 63

Juvenile neuronal ceroid lipofuscinosis is a lysosomal storage disease that causes visual impairment, progressive mental deterioration, and eventually death. A predominant 1.02-kb deletion as well as other mutations have been described in the CLN3 gene. Lacking significant identity with proteins of known function and no overt targeting signals within the primary amino acid sequence, accurate predictions of the intracellular location and function could not be made. Further, recent conflicting reports identified CLN3 as either a lysosomal or a mitochondrial protein. Transfection experiments using native and epitope-tagged fusion proteins were evaluated to help delineate CLN3 localization. We confirmed by immunohistochemistry and brefeldin A treatment that NH2-terminal green fluorescence protein (GFP)-CLN3 fusion proteins were retained in the Golgi apparatus, with no colocalization with mitochondrial markers. Anti-CLN3 antibodies directed against amino acids 67-90 of CLN3 were generated and shown to be specific for a 50-kDa protein in HEK 293 cells and GFP-CLN3 in transfected cells. However, cells transfected with nontagged CLN3 or carboxyl-terminal-tagged CLN3 were not immunoreactive with anti-CLN3 antibodies, suggesting that normally, the amino terminus interacts with other molecules. Thus, tags on the NH2-terminus probably inhibited these interactions and movement of CLN3 from the Golgi to more distal compartments. Also, CLN3 tagged at the COOH-terminus with either GFP or FLAG epitopes were retained in the ER, indicating a role for the COOH-terminus in trafficking. Taken together, these data confirm that CLN3 traffics through the ER and Golgi.
Mol Genet Metab 1999 Apr
PMID:Intracellular trafficking of the JNCL protein CLN3. 1019 Nov 11


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