Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers

Morrone, Amelia; Cavicchi, Catia; Bardelli, Tiziana; Antuzzi, Daniela; Parini, Rossella; Rocco, Maja Di; Feriozzi, Sandro; Gabrielli, Orazio; Barone, Rita; Pistone, Giuseppe; Spisni, C; Ricci, Roberta; Zammarchi, Enrico

doi:10.1136/jmg.40.8.e103

Cited by 62 publications

(63 citation statements)

References 29 publications

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“…The oligonucleotides and the amplifying conditions have been described previously. 7,18 The PCR products were checked on 2% agarose gels, excised and purified using Nucleospin Extract kit (Macherey-Nagel, Düren, Germany). Sequencing reactions were performed using the ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, USA), as recommended by the manufacturer.…”

Section: Analysis Of Genomic Dnamentioning

confidence: 99%

“…18 The new c.124A4G (M42V) sequence variation was investigated by restriction analysis with the NcoI enzyme (Fermentas, Canada) whose canonical restriction site was lost in the mutated specimen.…”

Section: Analysis Of Genomic Dnamentioning

confidence: 99%

“…Reversetranscriptase PCR (RT-PCR) was performed with the amplification primers described previously. 18 Cycle conditions were the same as those used for the analysis of genomic DNA.…”

Section: Rna Isolation and Analysesmentioning

confidence: 99%

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Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

et al. 2008

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Total or partial deficiency of the human lysosomal hydrolase a-galactosidase A is responsible for Fabry disease, the X-linked inborn error of glycosphingolipid metabolism. Together with the predominant a-galactosidase A gene mRNA product encoding the lysosomal enzyme, a weakly regulated alternatively spliced a-galactosidase A transcript is expressed in normal tissues, but its overexpression, due to the intronic g.9331G4A mutation, leads to the cardiac variant. We report the molecular characterization of five Fabry patients including two siblings. Sequencing analysis of the a-galactosidase A gene coding region and intron/exon boundaries identified the new c.124A4G (p.M42V) genetic lesion as well as a known deletion in three patients, whereas in the two remaining patients, no mutations were identified. To evaluate possible a-galactosidase A gene transcription alterations, both predominant and alternatively spliced mRNAs were quantified by absolute real-time PCR on total RNA preparations from the patients' fibroblasts. An impressive reduction in the predominant a-galactosidase A transcript was detected in the last patients (Pt 4 and Pt 5). However, the alternatively spliced mRNA was dramatically overexpressed in one of them, carrying a new intronic lesion (g.9273C4T). These findings strongly suggest a correlation between this new intronic mutation and the unbalanced a-galactosidase A mRNAs ratio, which could therefore be responsible for the reduced enzyme activity causing Fabry disease. The real-time assay developed here to investigate the two a-galactosidase A mRNAs might play a crucial role in revealing possible genetic lesions and in confirming the pathogenetic mechanisms underlying Fabry disease.

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Section: Analysis Of Genomic Dnamentioning

confidence: 99%

Section: Analysis Of Genomic Dnamentioning

confidence: 99%

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Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

et al. 2008

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“…The X-chromosome inactivation analysis was performed by studying the polymorphic CAG repeats of the AR gene using the methylation-sensitive restriction enzymes HpaII and CfoI as previously reported. 18,19 Quantitative fluorescent multiplex-PCR (QFM-PCR) of the TAZ gene TAZ exons 1, 4, 6-7, 8-9 and 10-11 were each amplified in a multiplex reaction, together with the ACY12 fragment from Ferri et al 20 as an internal control peak. Primers used are detailed in Table 1.…”

Section: Determination Of the X-chromosome Linkage And X-inactivationmentioning

confidence: 99%

Intra-individual plasticity of the TAZ gene leading to different heritable mutations in siblings with Barth syndrome

et al. 2015

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Infantile-onset skeletal myopathy Barth syndrome (OMIM #302060) is caused by mutations in the X-linked TAZ gene and hence usually manifests itself only in hemizygous males. Confirmatory testing is provided by mutational analysis of the TAZ gene and/or by biochemical dosage of the monolysocardiolipin/tetralinoleoyl cardiolipin ratio. Heterozygous females do not usually display a clinical phenotype but may undergo molecular genetic prenatal diagnosis during pregnancy. We characterized two novel and non-identical TAZ gene rearrangements in the offspring of a single female carrier of Barth syndrome. The hg19chrX:g.153634427_153644361delinsKP_123427.1 TAZ gene rearrangement was identified in her affected son, whereas the NM_000116.3(TAZ)c. − 72_109+51del TAZ gene deletion was identified in a male foetus during a subsequent pregnancy. The unaffected mother was surprisingly found to harbour both variants in addition to a wild-type TAZ allele. A combination of breakpoint junction sequencing, linkage analysis and assessment of allelic dosage revealed that the two variants had originated independently from an apparently unstable/mutable TAZ maternal allele albeit via different mutational mechanisms. We conclude that molecular prenatal diagnosis in Barth syndrome families with probands carrying TAZ gene rearrangements should include investigation of the entire coding region of the TAZ gene. The identification of the breakpoint junctions of such gross gene rearrangements is important to ensure accurate ascertainment of carriership with a view to providing appropriate genetic counselling.

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“…Even females with random X inactivation patterns (28) are symptomatic. Unfavorably skewed X inactivation may result in a high severity of disease manifestations (29,30). Age at onset of symptoms in females is generally older and more variable than in males.…”

Section: Heterozygotesmentioning

confidence: 99%

Fabry Disease: Treatment and diagnosis

Rozenfeld

2009

IUBMB Life

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SummaryFabry disease is an X-linked lysosomal disorder that results from a deficiency of the lysosomal enzyme a-galactosidase A leading to accumulation of glycolipids, mainly globotriaosylceramide in the cells from different tissues. Classical Fabry disease affects various organs. Clinical manifestations start at early age and include angiokeratoma, acroparesthesia, hypohydrosis, heat/exercise intolerance, gastrointestinal pain, diarrhea, and fever. The main complications of Fabry disease are more prominent after the age of 30 when kidney, heart, and/or cerebrovascular disorders appear. Most of the heterozygous females are symptomatic. Enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated. Quality of life of patients receiving ERT is improved. Enzyme replacement stabilizes or slows the decline in renal function and reduces left ventricular hypertrophy. Fabry disease may be underdiagnosed because of nonspecific and multiorgan symptoms. Different screening strategies have been carried out in different at-risk populations in order to detect undiagnosed Fabry patients. An increasing knowledge about Fabry disease within the medical community increases the chances of patients to receive a timely diagnosis and, consequently, to access the appropriate therapy.

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Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers

Cited by 62 publications

References 29 publications

Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

Unbalanced GLA mRNAs ratio quantified by real-time PCR in Fabry patients' fibroblasts results in Fabry disease

Intra-individual plasticity of the TAZ gene leading to different heritable mutations in siblings with Barth syndrome

Fabry Disease: Treatment and diagnosis

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