Mutation analysis of 28 gaucher disease patients: The Australasian experience

Lewis, Barry; Nelson, Paul V.; Evelyn, Fuentes Smith Lisset; Robertson, Claire A.; Morris, Phillip

doi:10.1016/s0031-3025(16)35536-2

Cited by 5 publications

(5 citation statements)

References 7 publications

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“…Such alleles apparently can arise from rearrangements with the GCase pseudogene [Zimran et al, 1990]. The L444P/complex or complex/complex genotypes are associated with severe neuronopathic Gaucher disease or perinatal lethality [Sidransky et al, 1992; Lewis et al, 1994]. Based on such associations, symptoms of severe and mild alleles have been proposed [Beutler and Gelbart, 1996].…”

Section: Introductionmentioning

confidence: 99%

Gaucher disease: In vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes

Zhao

Bailey

Elsas

et al. 2002

American J of Med Genetics Pt A

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Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.

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Section: Introductionmentioning

confidence: 99%

Gaucher disease: In vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes

Zhao

Bailey

Elsas

et al. 2002

American J of Med Genetics Pt A

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“…Several of these are more frequently encountered in specific populations. There are many published series describing genotypic analyses of patients with Gaucher disease from different ethnic backgrounds or geographic locations, including the Ashkenazi Jews [Beutler et al, 1992; Horowitz et al, 1998], patients from Japan, [Hiroyuki et al, 1996; Eto and Ida, 1998], China [Choy et al, 1999], Australia [Lewis et al, 1994], Great Britain [Hatton et al, 1997], Spain [Cormand et al, 1998a], Portugal [Amaral et al, 1993], Poland [TylkiSzymanska et al, 1996], France [Germain et al, 1998], Argentina [Cormand et al, 1998b], the Netherlands [Boot et al, 1997], and the Czech and Slovak Republics [Hodaňová et al, 1999].…”

Section: Introductionmentioning

confidence: 99%

Glucocerebrosidase mutations among African-American patients with type 1 Gaucher disease

et al. 2001

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While the inherited deficiency of the enzyme glucocerebrosidase (Gaucher disease) is panethnic in its distribution, there have not been studies of the mutations encountered in specific ethnic groups in the United States, other than those on Ashkenazi Jews. We present the clinical descriptions and genotypes of seven patients of African-American ancestry with type 1 Gaucher disease, and summarize the published literature regarding the genotypes encountered in this population. All seven of the patients had moderate-to-severe manifestations of the disease, and all developed symptoms by adolescence. Genotypic analyses revealed that no two probands shared the same genotype. The common mutations N370S, c.84-85insG, IVS2+1 G-->A, and R463C were not seen. Mutation L444P was present on one allele in each of the patients; but the same mutation was encountered as a single point mutation in three of the patients, and as part of a recombinant allele in four of the patients. Southern blot analyses revealed a glucocerebrosidase fusion allele in one patient, and a duplication resulting from recombination in the region downstream from the glucocerebrosidase gene in three of the patients. Five different point mutations (A90T, R48W, N117D, R170C, and V352L), one deletion mutation (c.222-224 delTAC), and one insertion mutation (c.153-154 insTACAGC) were encountered. Our results demonstrate that there is significant genotypic heterogeneity among African-American patients with type 1 Gaucher disease, and that recombinations in the glucocerebrosidase gene locus are particularly common in this patient group. Published 2001 Wiley-Liss, Inc.

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“…16 In humans, L444P/L444P homozygosity is compatible with survival, albeit with a propensity to develop CNS disease. 25,26 Thus, unlike the mouse models for other lysosomal diseases, the knock-out mouse for Gaucher disease has not proved highly useful for detailed pathophysiologic studies.…”

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confidence: 99%

Viable Mouse Models of Acid β-Glucosidase Deficiency

Quinn

Witte

et al. 2003

The American Journal of Pathology

150

228

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Gaucher disease is an autosomal recessively inherited disease caused by mutations at the acid beta-glucosidase (GCase) locus (GBA). To develop viable models of Gaucher disease, point mutations (pmuts), encoding N370S, V394L, D409H, or D409V were introduced into the mouse GCase (gba) locus. DNA sequencing verified each unique pmut. Mutant GCase mRNAs were near wild-type (WT) levels. GCase activities were reduced to 2 to 25% of WT in liver, lung, spleen, and cultured fibroblasts from pmut/pmut or pmut/null mice. The corresponding brain GCase activities were approximately 25% of WT. N370S homozygosity was lethal in the neonatal period. For the other pmut mice, a few storage cells appeared in the spleen at > or =7 months (D409H or D409V homozygotes) or > or =1 year (V394L homozygotes). V394L/null, D409H/null, or D409V/null mice showed scattered storage cells in spleen at approximately 3 to 4 months. Occasional storage cells (sinusoidal cells) were present in liver. In D409V/null mice, large numbers of Mac-3-positive storage cells (ie, macrophages) accumulated in the lung. Glycosphingolipid analyses showed varying rates of progressive glucosylceramide accumulation in visceral organs of pmut/pmut or pmut/null mice, but not in brain. These GCase-deficient mice provide tools for gaining insight into the pathophysiology of Gaucher disease and developing improved therapies.

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Mutation analysis of 28 gaucher disease patients: The Australasian experience

Cited by 5 publications

References 7 publications

Gaucher disease: In vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes

Gaucher disease: In vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes

Glucocerebrosidase mutations among African-American patients with type 1 Gaucher disease

Viable Mouse Models of Acid β-Glucosidase Deficiency

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