Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family

Shamseddine, Ali; Taher, Ali T.; Fakhani, S.; Zhang, M.; Scott, C. Ronald; Habbal, Zuheir

doi:10.1002/ajmg.a.20518

Cited by 11 publications

(5 citation statements)

References 19 publications

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“…Five valine 3 leucine substitutions and one leucine 3 valine substitution have been discovered in patients with Gaucher disease (28,(41)(42)(43)(44)(45). The V394L GCase has major kinetic changes similar to those in N370S.…”

Section: Discussionmentioning

confidence: 99%

Analyses of Variant Acid β-Glucosidases

Liou

Kazimierczuk

Zhang

et al. 2006

Journal of Biological Chemistry

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117

132

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Acid ␤-glucosidase (GCase) is a 497-amino acid, membrane-associated lysosomal exo-␤-glucosidase whose defective activity leads to the Gaucher disease phenotypes. To move toward a structure/ function map for disease mutations, 52 selected single amino acid substitutions were introduced into GCase, expressed in an insect cell system, purified, and characterized for basic kinetic, stability, and activator response properties. The variant GCases from Gaucher disease patients and selected variant GCases from the mouse had decreased relative k cat and differential effects on active site binding and/or attachment of mechanism-based covalent (conduritol B epoxide) or reversible (deoxynojirimycin derivatives) inhibitors. A defect in negatively charged phospholipid activation was present in the majority of variant GCases but was increased in two, N370S and V394L. Deficits in saposin C enhancement of k cat were present in variant GCases involving residues 48 -122, whereas ϳ2-fold increases were obtained with the L264I GCase. About 50% of variant GCases each had wild-type or increased sensitivity to in vitro cathepsin D digestion. Mapping of these properties onto the crystal structures of GCase indicated wide dispersion of functional properties that can affect catalytic function and stability. Site-directed mutagenesis of cysteine residues showed that the disulfide bonds, Cys 4 -Cys 16 and Cys 18 -Cys 23 , and a free Cys 342 were essential for activity; the free Cys 126 and Cys 248 were not. Relative k cat was highly sensitive to a His substitution at Arg 496 but not at Arg 495 . These studies and high phylogenetic conservation indicate localized and general structural effects of Gaucher disease mutations that were not obvious from the nature of the amino acid substitution, including those predicted to be nondisruptive (e.g. Val 3 Leu). These results provide initial studies for the engineering of variant GCases and, potentially, molecular chaperones for therapeutic use.

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Section: Discussionmentioning

confidence: 99%

Analyses of Variant Acid β-Glucosidases

Liou

Kazimierczuk

Zhang

et al. 2006

Journal of Biological Chemistry

Self Cite

117

132

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“…3) [23]. A novel GC variant, L371V, has recently been discovered in a Lebanese family causing symptoms that were more severe than those associated with the common N370S mutation [24]. It is worthwhile to note that much more is known about mutations associated with Gaucher disease patients of European descent than there is of patients originating from other parts of the world.…”

Section: Gaucher Diseasementioning

confidence: 98%

Therapeutic strategies to ameliorate lysosomal storage disorders – a focus on Gaucher disease

Sawkar

D’Haeze

Kelly

2006

Cell. Mol. Life Sci.

120

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The lysosomal storage disorders encompass more than 40 distinct diseases, most of which are caused by the deficient activity of a lysosomal hydrolase leading to the progressive, intralysosomal accumulation of substrates such as sphingolipids, mucopolysaccharides, and oligosaccharides. Here, we primarily focus on Gaucher disease, one of the most prevalent lysosomal storage disorders, which is caused by an impaired activity of glucocerebrosidase, resulting in the accumulation of the glycosphingolipid glucosylceramide in the lysosomes. Enzyme replacement and substrate reduction therapies have proven effective for Gaucher disease cases without central nervous system involvement. We discuss the promise of chemical chaperone therapy to complement established therapeutic strategies for Gaucher disease. Chemical chaperones are small molecules that bind to the active site of glucocerebrosidase variants stabilizing their three-dimensional structure in the endoplasmic reticulum, likely preventing their endoplasmic reticulum-associated degradation and allowing their proper trafficking to the lysosome where they can degrade accumulated substrate to effectively ameliorate Gaucher disease.

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“…Multigenerational GD has been reported in two separate Lebanese families [18,19], but in both families, there was a high degree of consanguinity. Kolodny et al [20] reported an Ashkenazi Jewish family with three generations of GD; there was no mention of consanguinity, but there was compound heterozygosity in three of the individuals.…”

Section: Discussionmentioning

confidence: 99%

Three cases of multi-generational Gaucher disease and colon cancer from an Ashkenazi Jewish family: A lesson for cascade screening

Hannah‐Shmouni

Amato

2019

Molecular Genetics and Metabolism Reports

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Gaucher disease (GD) is one of the commonest lysosomal storage diseases that is inherited in an autosomal recessive manner and affects 1 in 50,000 to 100,000 people in the general population. The frequency is much higher (1 in 500 to 1000) in people of Ashkenazi Jewish heritage due to a founder effect. GD is caused by decreased or absent activity of β-glucosidase with subsequent accumulation of the substrate glucosylceramide in macrophages due to genetic alterations in the GBA gene. These often accumulate in the spleen, liver and bone marrow. Three types exist, with type 1 being the most common, also referred to as non-neuronopathic GD. A broad clinical spectrum exists; patients of any age may manifest with hepatosplenomegaly, anaemia, thrombocytopenia, lung disease, bone abnormalities or may remain asymptomatic throughout their lifespan. Multi-generational disease does not usually occur because the risk of disease with each pregnancy, presuming both parents are carriers of the condition, is 25%. Herein, we report an Ashkenazi Jewish family with multi-generational GD type 1 and multigenerational colon cancer in the same three individuals, and reinforce the importance of cascade screening in families with genetic conditions.

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Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family

Cited by 11 publications

References 19 publications

Analyses of Variant Acid β-Glucosidases

Analyses of Variant Acid β-Glucosidases

Therapeutic strategies to ameliorate lysosomal storage disorders – a focus on Gaucher disease

Three cases of multi-generational Gaucher disease and colon cancer from an Ashkenazi Jewish family: A lesson for cascade screening

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