A Novel Missense Mutation (W797R) in the Myophosphorylase Gene in Spanish Patients With McArdle Disease

Fernández, Roberto; Navarro, Carmen; Andreu, Antonio Lorenzo; Bruno, Claudio; Shanske, Sara; Gamez, Josep; Teijeira, Susana; Hernández, I.; Teijeiro, Alfonso; Fernández, José M.; Musumeci, Olimpia; DiMauro, Salvatore

doi:10.1001/archneur.57.2.217

Cited by 17 publications

(12 citation statements)

References 23 publications

(12 reference statements)

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“…The W797R mutation was observed in 16.5% of our patients (9 of 54), accounting for 13.7% of mutant alleles (15 of 108). This mutation has only been reported in Spanish patients and seems to be frequent in this population 20, 30…”

Section: Discussionmentioning

confidence: 80%

Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study

Martín

Rubio

Buchbinder

et al. 2001

Annals of Neurology

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We report on 54 Spanish patients with McArdle's disease from 40 unrelated families. Molecular analysis revealed that the most common R49X mutation was present in 70% of patients and 55% of alleles. The G204S mutation was less frequent and found in 14.8% of patients and 9% of mutant alleles. The W797R mutation was observed in 16.5% of patients, accounting for 13.7% of mutant alleles. Moreover, 78% of mutant alleles among Spanish patients can be identified by using polymerase chain reaction-restriction fragment length polymorphism analysis for the R49X, G204S, and W797R mutations, which makes noninvasive diagnosis possible through molecular genetic analysis of blood DNA. Six novel mutations were found. Three were missense mutations, E348K, R601W, and A703V; two nonsense mutations, E124X and Q754X; and one single base pair deletion, 533 delA. No clear genotype-phenotype correlation emerges from our study. Most of the mutations of uncharged and solvent inaccessible residues and the truncations must disrupt the basic structure of the protein. The mutations of charged residues would be expected to interfere with internal hydrogen bonding networks, introducing severe incompatible partnering that is caused by poor packing or electrostatic repulsions.

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Section: Discussionmentioning

confidence: 80%

Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study

Martín

Rubio

Buchbinder

et al. 2001

Annals of Neurology

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“…For instance, a diagnostic flowchart was proposed for Spanish patients [Rubio et al., ] that is likely to make diagnosis faster and cheaper. Specific PCR‐RFLP designs have been developed for identification of common PYGM pathogenic mutations such as p.R50X, p.G205S, or p.W798R, whose presence can be evidenced by the digestion with the enzymes Nla III [Tsujino et al., ], Hae III [Fernandez et al., ], and Bsr BI [Fernandez et al., ], respectively. Although obviously not all mutations can be detected with the above‐mentioned approach, it is still a useful method to precede the sequencing reaction [Rubio et al., ; Vieitez et al., ].…”

Section: Clinical and Diagnosis Relevancementioning

confidence: 99%

McArdle Disease: Update of Reported Mutations and Polymorphisms in thePYGMGene

et al. 2015

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McArdle disease is an autosomal-recessive disorder caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (or "myophosphorylase"), which catalyzes the first step of glycogen catabolism, releasing glucose-1-phosphate from glycogen deposits. As a result, muscle metabolism is impaired, leading to different degrees of exercise intolerance. Patients range from asymptomatic to severely affected, including in some cases, limitations in activities of daily living. The PYGM gene codifies myophosphoylase and to date 147 pathogenic mutations and 39 polymorphisms have been reported. Exon 1 and 17 are mutational hot-spots in PYGM and 50% of the described mutations are missense. However, c.148C>T (commonly known as p.R50X) is the most frequent mutation in the majority of the studied populations. No genotype-phenotype correlation has been reported and no mutations have been described in the myophosphorylase domains affecting the phosphorylated Ser-15, the 280's loop, the pyridoxal 5'-phosphate, and the nucleoside inhibitor binding sites. A newly generated knock-in mouse model is now available, which renders the main clinical and molecular features of the disease. Well-established methods for diagnosing patients in laboratories around the world will shorten the frequent ∼20-year period stretching from first symptoms appearance to the genetic diagnosis.

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“…Screening for the mutations p.R50X, p.G205S, and p.W798R were performed by PCR-RFLP using methods described elsewhere (Fernandez et al 2000, Tsujino et al 1993 To avoid false positive PCR-RFLP results, we verified the nucleotide change in each mutation by direct sequencing of a second amplified PCR product. Both strands were sequenced in both directions using the conditions described below with the ABIDyeDeoxy Terminator Cycle Sequencing kit (Applied Biosystems, Foster City, CA, U.S.A., www.appliedbiosystems.com).…”

Section: Genomic Dna Extraction and Screening For Three Known Mutationsmentioning

confidence: 99%

A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients

Rubio¹,

García‐Consuegra²,

Nogales‐Gadea³

et al. 2007

Hum. Mutat.

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A Novel Missense Mutation (W797R) in the Myophosphorylase Gene in Spanish Patients With McArdle Disease

Abstract: The W797R missense mutation is the third novel mutation to be identified among Spanish patients. Its relative frequency suggests that it should be added to the R49X mutation in the molecular screening of McArdle disease in Spain.

Cited by 17 publications

References 23 publications

Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study

Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study

McArdle Disease: Update of Reported Mutations and Polymorphisms in thePYGMGene

A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients

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