Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic findings such as hepatosplenomegaly and typical Gaucher storage cells in a bone marrow aspirate led to the clinical diagnosis of Gaucher's disease in the seven-year old patient described in this report. On the basis of the lack of neurologic involvement the child was classified as having the Type 1, nonneurologic form of Gaucher's disease. After splenectomy glucocerebrosidase was extracted from her spleen for biochemical analysis. As expected, a marked deficiency of glucocerebrosidase activity was evident in the splenic extract, however her enzyme displayed anomalous behavior compared to other identical splenic preparations from documented Type 1 Gaucher's disease patients in that it failed to reconstitute with the acidic lipid phosphatidylserine. Using the polymerase chain reaction (PCR)-based color complementation assay and restriction endonuclease analysis, we compared the mutation genotype of this child with that of five other classical Type 1 patients. This analysis revealed that our patient alone was homoallelic for a T----C transition at position 1448 in the glucocerebrosidase cDNA that results in a 444Leu----Pro substitution in the glucocerebrosidase protein. The latter mutation genotype is normally associated with the neurologic phenotype, namely, the Types 2 and 3 forms of the disease. The relevance of the nature of polarity in clinical and biochemical analyses is discussed with regard to the phenotypic classification and the future clinical course of disease in the child.
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PMID:A case of nonneurologic Gaucher's disease that biochemically resembles the neurologic types. 167 7

To search for a genetic marker for type 2 Gaucher's disease (acute neuronopathic form), we compared the nucleotide sequence of a cloned glucocerebrosidase gene from a patient with Gaucher's disease with a normal gene. We found only a single base substitution (T----C) in exon X. This mutation results in the substitution of proline for leucine in position number 444 and produces a new cleavage site for the NciI restriction endonuclease. We analyzed NciI enzymatic digests of genomic DNA from 20 patients with type 1, 5 with type 2, and 11 with type 3 Gaucher's disease, and 29 normal controls for a restriction-fragment-length polymorphism (RFLP). Four of 5 patients with type 2 disease and all 11 with type 3 disease had at least one allele with the mutation. Two of 5 patients with type 2 disease and 7 of 11 with type 3 were homozygous for this mutation. Only 4 of 20 patients with type 1 Gaucher's disease had the mutant allele and were heterozygous for it. None of the 29 normal controls had the mutant allele. The high frequency of this mutation (444leucine----proline) in patients with neuronopathic Gaucher's disease, detectable by the NciI RFLP, may be of value in the identification of patients who will have the neurologic sequelae of Gaucher's disease.
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PMID:A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. 288 Feb 91

Two sisters with moderately severe Gaucher disease were diagnosed as having the usually relatively benign 1226G/1226G genotype by examination of DNA amplified from exon 9, where this mutation is located. Because of the discrepancy between the apparent genotype and the phenotype, we suspected that one of the alleles had not amplified. Therefore, the DNA of both parents was examined. The father was heterozygous for the 1226G mutation but the mother did not have this abnormality. It was shown that the mother and both daughters had a deletion of the glucocerebrosidase gene: only about one-half of the polymerase chain reaction (PCR) amplification product of the glucocerebrosidase gene in this region was found, compared to internal controls consisting of the glucocerebrosidase pseudogene and of the adjacent liver pyruvate kinase (PKLR) gene. The appearance of Southern blots developed with full length glucocerebrosidase cDNA probes showed that the band unique to the functional glucocerebrosidase gene had reduced intensity, and no abnormal bands were present after digestion with any restriction endonuclease, indicating that the entire coding region was deleted.
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PMID:Erroneous assignment of Gaucher disease genotype as a consequence of a complete gene deletion. 783 51

Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the glucocerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genomic DNA nucleotide position 6683) from a Gaucher disease patient of Jewish-Polish-Russian descent with type 1 Gaucher disease. It is a G-->A transition in exon 11 that results in 496Arg-->496His of glucocerebrosidase. This missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A-->G transition at cDNA nucleotide position 1226 which creates an XhoI cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish-Polish-Russian descent. 791 32

Gaucher disease is the most prevalent sphingolipidosis, characterized by genetic deficiency of lysosomal hydrolase glucocerebrosidase, and is inherited in an autosomal recessive manner. To characterize the molecular basis of Gaucher disease in Japan, we analyzed for the presence of the two known mutations (1448C and 754A) in the glucocerebrosidase gene of 15 patients (14 families) with Gaucher disease by selective amplification and restriction endonuclease analysis. We found that the 1448C and 754A mutations occurred in all three clinical subtypes of Japanese Gaucher disease patients. The 1448C mutation was found on 12 (40%) out of 30 chromosomes (44% allele frequency in nonneuronopathic form, and 33% in neuronopathic forms), while homozygosity for this mutation was only found in two nonneuronopathic patients (age of 1 year 6 months and 7 years). We detected the 754A mutation on 6 (20%) out of 30 chromosomes. No patient was homozygous for 754A mutation. Furthermore, we identified four patients who were compound hetrozygote for 754A and 1448C. One of these was a type 3 Gaucher patient, but the other three patients were free from central nervous system manifestations at the time of observation. These results indicate that phenotypic presentation of Gaucher disease including the presence of nervous manifestation, progression, and severity of disease, may be affected by other genetic, environmental, or developmental factors, as well as the glucocerebrosidase genotype.
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PMID:Molecular screening of Japanese patients with Gaucher disease: phenotypic variability in the same genotypes. 825 89

Three novel point mutations were detected in the glucocerebrosidase gene of three unrelated Gaucher's disease patients by direct sequencing of PCR products. The first is a C to G change at position 4263 in the genomic sequence (exon 7) which results in a proline to arginine change at position 266 in the mature enzyme (P266R). The second is a G to C change at position 5276 in the genomic sequence (exon 8) which results in an aspartic acid to histidine change at position 315 (D315H). The third is a C to A change at position 5286 in the genomic sequence (exon 8) which results in an alanine to aspartic acid change at position 318 (A318D). The first mutation destroys an AvaII restriction endonuclease site, the second creates a BspMI site and the third creates a BamH I site.
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PMID:Three unrelated Gaucher's disease patients with three novel point mutations in the glucocerebrosidase gene (P266R, D315H and A318D). 854 70

Gaucher disease is the most prevalent lysosomal storage disorder. It is autosomalrecessive, resulting in lysosomal glucocerebrosidase deficiency. Three clinical forms of Gaucher disease have been described: type 1 (nonneuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). We performed PCR-thermal cycle sequence analysis of glucocerebrosidase genomic DNA and identified a novel mutation in a non-Jewish type 1 Gaucher disease patient. It is a C insertion in exon 3 at cDNA nucleotide position 122 and genomic nucleotide position 1626. This mutation causes a frameshift and, subsequently, four of the five codons immediately downstream of the insertion were changed while the sixth was converted to a stop codon, resulting in premature termination of protein translation. The 122CC insertion abolishes a Cac81 restriction endonuclease cleavage site, allowing a convenient and reliable method for detection using RFLP analysis of PCR-amplified glucocerebrosidase genomic DNA. The mutation in the other Gaucher allele was found to be an A-->G substitution at glucocerebrosidase cDNA nucleotide position 1226 that so far has only been reported among type 1 Gaucher disease patients. Since mutation 122CC causes a frameshift and early termination of protein translation, it most likely results in a meaningless transcript and subsequently no residual glucocerebrosidase enzyme activity. We speculate that mutation 122CC may result in a worse prognosis than mutations associated with partial activity. When present in the homozygous form, it could be a lethal allele similar to what has been postulated for the other known insertion mutation, 84GG. Our patient, who is a compound heterozygote 122CC/1226G, has moderately severe type 1 Gaucher disease. Her clinical response to Ceredase therapy that began 31 months ago has been favorable, though incomplete.
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PMID:Novel insertion mutation in a non-Jewish Caucasian type 1 Gaucher disease patient. 902 60

Gaucher disease is the most prevalent lysosomal storage disease. It is panethnic and results from an inherited deficiency of glucocerebrosidase. Most mutations to date have been identified among Jewish and non-Jewish Caucasian patients; mutations in Chinese patients are largely unknown. We have performed nucleotide sequence analysis of PCR-amplified glucocerebrosidase genomic DNA from five unrelated Chinese patients affected with type 1 (non-neuropathic) Gaucher disease. A novel heterozygous C --> T mutation at cDNA nucleotide position 475 (R120W) was detected in a patient who is also heterozygous for a C --> T transition at cDNA nucleotide position 259 (R48W). In a second patient, a novel, heterozygous T --> G transversion at cDNA 226 (F37V) was detected. Mutation 1448 (L444P), the most prevalent mutation among non-Jewish Caucasian Gaucher patients, was found in the heterozygous form in four patients. The mutations in the second Gaucher allele in the other three patients are mutations 254 (G46E), 680 (N188S), and 754 (F213I), which were recently reported in Korean, Arab, and Chinese (Taiwanese) patients. We have developed screening methods that utilize PCR amplification of glucocerebrosidase genomic DNA and Eco571, Nci1, Hinc11, BsaJ1, and Bsr1 restriction endonuclease analyses for the detection of each of these mutations. The population genetics of some of these Gaucher alleles and their implications in genotype/phenotype correlation are discussed.
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PMID:Identification of two novel and four uncommon missense mutations among chinese Gaucher disease patients. 921 17

Gaucher disease is the most prevalent inherited sphingolipidosis and results from deficient glucocerebrosidase activity. Three clinical forms of Gaucher disease have been described: type 1, or non-neuronopathic; type 2, or acute neuronopathic; and type 3, or subacute neuronopathic. We have identified a novel mutation in a patient of Russian-British descent who died of type 2 Gaucher disease a few hours after birth. A heterozygous T --> C transition mutation in exon 6, cDNA nucleotide position 667, results in the substitution of tryptophan by arginine at amino acid residue 184 (W184R) of glucocerebrosidase. This mutation creates a new cleavage site for the restriction endonuclease Hinf1. We developed a method that utilizes Hinf1 restriction endonuclease analysis to confirm the presence of the mutation and test family members. The second mutation identified in the other glucocerebrosidase allele of the patient is mutation L444P, a severe mutation frequent in type 2 and 3 Gaucher disease. Since the patient died very shortly after birth, we postulate that the W184R/L444P genotype may result in little or no detectable glucocerebrosidase activity and thus a poor prognosis.
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PMID:Novel point mutation (W184R) in neonatal type 2 Gaucher disease. 1067 38

Parkinson's disease (PD) has widely been reported to be associated with mutations in the PARK genes. To investigate potential genetic risk factors for PD in a northern Han Chinese population, six single nucleotide polymorphisms (SNP) (R366W, V380L, P196S, R1628P, G2385R and R461W) located in four PARK genes were multiplex-amplified in two independent polymerase chain reaction (PCR) systems. Restriction fragment length polymorphisms (RFLP) were subsequently genotyped with Hae III endonuclease digestion in samples from 202 patients with PD and 212 control participants. High-throughput, multiplexed PCR-RFLP assays were able to accurately identify all six SNP. The genotypic frequency of G2385R in PARK8 was significantly different between the patient and control groups; however, the remaining SNP were not associated with PD. No heterogeneity was observed in the R461W site, and only one P196S site was found in the patient group. The polymorphic sites R366W and V380L and R1628P and G2385R were not in linkage disequilibrium. Carriers of 2385R presented at a higher Hoehn-Yahr stage compared to non-carriers. This study demonstrated an association of the G2385R allele with risk for PD in a northern Han Chinese population.
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PMID:Association of Parkinson's disease with six single nucleotide polymorphisms located in four PARK genes in the northern Han Chinese population. 2257 62


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