GLA variation p.E66Q identified as the genetic etiology of Fabry disease using exome sequencing

Peng, Hao; Xu, Xiaojuan; Zhang, Lusi; Zhang, Xuehong; Peng, Hui; Zheng, Yu; Luo, Sanchuan; Guo, Hui; Xia, Kun; Li, Jia‐Da; Yao, Hongliang; Hu, Zhengmao

doi:10.1016/j.gene.2015.09.088

Cited by 12 publications

(12 citation statements)

References 14 publications

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“…Sakuraba and coworkers measured the activity in 20 Japanese or Korean male carriers with renal and cardiovascular disorders and found 13% to 26% of the normal mean values for plasma and 24% to 65% of the normal mean values for white blood cells, but the lyso-Gb3 levels were as low as those of healthy controls and no inclusion bodies were found [62]. Hu and co-workers found that the mutation segregated with renal disease in a very large Chinese family, but they did not measure the accumulation of the substrate or of lyso-Gb3 in the same patients [76]. The involvement in cardiovascular disease has also been suspected, but no accumulation of Gb3 was found in the heart of a patient carrying E66Q [77].…”

Section: Resultsmentioning

confidence: 99%

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

Citro

Cammisa

Liguori

et al. 2016

IJMS

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Fabry disease is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum. Missense mutations pose a special problem for graduating diagnosis and choosing a cost-effective therapy. Some mutants retain enzymatic activity, but are less stable than the wild type protein. These mutants can be stabilized by small molecules which are defined as pharmacological chaperones. The first chaperone to reach clinical trial is 1-deoxygalactonojirimycin, but others have been tested in vitro. Residual activity of GLA mutants has been measured in the presence or absence of pharmacological chaperones by several authors. Data obtained from transfected cells correlate with those obtained in cells derived from patients, regardless of whether 1-deoxygalactonojirimycin was present or not. The extent to which missense mutations respond to 1-deoxygalactonojirimycin is variable and a reference table of the results obtained by independent groups that is provided with this paper can facilitate the choice of eligible patients. A review of other pharmacological chaperones is provided as well. Frequent mutations can have residual activity as low as one-fourth of normal enzyme in vitro. The reference table with residual activity of the mutants facilitates the identification of non-pathological variants.

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Section: Resultsmentioning

confidence: 99%

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

Citro

Cammisa

Liguori

et al. 2016

IJMS

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“…As with many genetic diseases, the spectrum of phenotypes among patients with the same GLA mutation can vary widely [4,8]. According to previous reports, the classic form of Fabry disease starts in childhood or adolescence and usually includes symptoms such as angiokeratoma, acroparesthesia, abdominal pain, corneal opacities, hypohidrosis, hearing disorders, cardiac lesions, renal insufficiency, and stroke, leading to high morbidity and mortality [5,8,9]. Patients with variant forms typically present milder clinical manifestations, mostly limited to the heart or the kidneys.…”

Section: Introductionmentioning

confidence: 99%

Genotype–Phenotype Correlation in a New Fabry-Disease-Causing Mutation

et al. 2019

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Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical activity, and periodic cardiac arrhythmia. Echocardiography revealed left ventricular hypertrophy with normal diastolic function. The patient had experienced acroparesthesia in her upper limbs and abdominal pain since childhood, and in the last decade had experienced mild proteinuria without renal failure. Her renal biopsy was typical for Fabry disease. The patient’s brain magnetic resonance imaging (MRI) (T2 flair) showed white matter hyperintensities lesions. DNA sequencing of the proband, her mother and one of her sons showed a novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp). All three patients had decreased α-galactosidase A activity and specific FD manifestations. Conclusions: A novel GLA mutation, c.270C>G (p.Cys90Trp), was found in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac involvement. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.

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“…The GLA gene encoding α-Gal A is located on the long arm of the X chromosome (Xq22.1) is 12 kb in length, with 7 exons. Hundreds of mutations in G LA, including missense and nonsense mutations and splicing defects, have been associated with FD, most of which are unique (“private mutations”) in each novel proband [9–11]. The pharmacological chaperone Migalastat was approved only recently, first by the EMA in Europe and then by the FDA, whereas enzyme replacement therapy (ERT) has effectively been available since 2001.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel loss-of-function mutation of the GLA gene in a Chinese Han family with Fabry disease

et al. 2018

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BackgroundFabry disease is an X-linked recessive lysosomal disorder caused by deficient enzymatic activity of α-galactosidase A (α-Gal A). The insufficient enzymatic activity leads to excessive accumulation of glycosphingolipids, the substrates of the enzyme, in lysosomes in organs and tissues. Mutations in the α-Gal A gene (GLA, Xq22) have been proven to be responsible for Fabry disease.MethodsIn this study, we report a four-generation pedigree with left ventricular hypertrophy and chronic renal failure that was diagnosed by sequencing the GLA gene. An over expression system was constructed to evaluate the function of the detected mutation.ResultsWe identified a novel mutation in exon 6 of the GLA gene, p.Asn278Lys, which completely co-segregated with the disease phenotype. The protein level of α-Gal A was significantly lower in the variant group than in the wild-type group; additionally, the pharmacological chaperone 1-deoxy-galactonojirimycin (DGJ) effectively normalized the enzyme activity of α-Gal A and its decline at the protein level.ConclusionsThis study is the first to report a novel loss-of-function mutation, p.Asn278Lys, in exon 6 of the GLA gene as a genetic aetiology for Fabry disease. In addition, we analysed the feasibility of DGJ as a therapeutic approach for this particular GLA mutation.

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GLA variation p.E66Q identified as the genetic etiology of Fabry disease using exome sequencing

Cited by 12 publications

References 14 publications

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

The Large Phenotypic Spectrum of Fabry Disease Requires Graduated Diagnosis and Personalized Therapy: A Meta-Analysis Can Help to Differentiate Missense Mutations

Genotype–Phenotype Correlation in a New Fabry-Disease-Causing Mutation

Identification of a novel loss-of-function mutation of the GLA gene in a Chinese Han family with Fabry disease

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