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Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.

ABSTRACT: Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type 1 Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type 3 Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations (A90T, N117D, T134I, Y135X, R170C, W184R, A190T, Y304X, A341T, D399Y, c.153-154insTACAGC, c.203-204insC, c.222-224delTAC, and c.1122-1123insTG) and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Although 93% of the mutant alleles in our Ashkenazi Jewish type 1 patients were N370S, c.84-85insG, IVS2+1G-->A or L444P, these four mutations accounted for only 49% of mutant alleles in the non-Jewish type 1 patients. Genotype-phenotype correlations were attempted. Homozygosity or heterozygosity for N370S resulted in type 1 Gaucher disease, whereas homozygosity for L444P was associated with type 3. Genotype L444P/recombinant allele resulted in type 2 Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease. The phenotypic consequences of other mutations, particularly R463C, were more inconsistent. Our results demonstrate a high rate of mutation detection, a large number of novel and rare mutations, and an accurate assessment of the prevalence of recombinant alleles. Although some genotype-phenotype correlations do exist, other genetic and environmental factors must also contribute to the phenotypes encountered, and we caution against relying solely upon genotype for prognostic or therapeutic judgements.

SUBMITTER: Koprivica V

PROVIDER: S-EPMC1378059 | biostudies-other | 2000 Jun

REPOSITORIES: biostudies-other

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Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.

Koprivica V V Stone D L DL Park J K JK Callahan M M Frisch A A Cohen I J IJ Tayebi N N Sidransky E E

American journal of human genetics 20000504 6

Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type ...[more]

PMID: 10796875

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Project description:BACKGROUND:Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20-40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality. METHODS:The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of ?-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula. RESULTS:The biochemical analysis revealed a significant reduction in the ?-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887. CONCLUSIONS:The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India.

Project description:Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients.Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier).The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism.The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years.The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism.

Dataset Information

Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.

Publications

Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.

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