A nonsense mutation in the myophosphorylase gene in a Japanese family with McArdle's disease

Bruno, Claudio; Tamburino, Lucia; Kawashima, Nozomu; Andreu, Antoni L.; Shanske, Sara; Hadjigeorgiou, George; Kawashima, Atsushi; DiMauro, Salvatore

doi:10.1016/s0960-8966(98)00096-0

Cited by 22 publications

(12 citation statements)

References 12 publications

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“…We searched this list of disease-causing mutations for sequences that were amenable for cloning into splicing reporter constructs and were present in exons of near average size and splice-site strength . Of the three different disease-causing mutations we selected-OPA1, PYGM, and TFR2-there was no a priori evidence for any effect on splicing from in vitro analysis (Bruno et al 1999;Camaschella et al 2000;Schimpf et al 2008). However, aberrant splicing of OPA1, PYGM, and TFR2 is observed in patients carrying coding and non-coding mutations at other positions in these genes (Schimpf et al 2006;Biasiotto et al 2008;Nogales-Gadea et al 2008).…”

Section: Functional Validation Of a Splicing Silencer Mutationally LImentioning

confidence: 99%

Loss of exon identity is a common mechanism of human inherited disease

Sterne-Weiler¹,

Howard²,

Mort³

et al. 2011

Genome Res.

160

155

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It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inherited disease is still poorly understood. Here we use a top-down approach to determine rates of loss or gain of known human exonic splicing regulatory (ESR) sequences associated with either disease-causing mutations or putatively neutral single nucleotide polymorphisms (SNPs). We observe significant enrichment toward loss of ESEs and gain of ESSs among inherited disease-causing variants relative to neutral polymorphisms, indicating that exon skipping may play a prominent role in aberrant gene regulation. Both computational and biochemical approaches underscore the relevance of exonic splicing enhancer loss and silencer gain in inherited disease. Additionally, we provide direct evidence that both SRp20 (SRSF3 ) and possibly PTB (PTBP1) are involved in the function of a splicing silencer that is created de novo by a total of 83 different inherited disease mutations in 67 different disease genes. Taken together, we find that~25% (7154/27,681) of known mis-sense and nonsense disease-causing mutations alter functional splicing signals within exons, suggesting a much more widespread role for aberrant mRNA processing in causing human inherited disease than has hitherto been appreciated.

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Section: Functional Validation Of a Splicing Silencer Mutationally LImentioning

confidence: 99%

Loss of exon identity is a common mechanism of human inherited disease

Sterne-Weiler¹,

Howard²,

Mort³

et al. 2011

Genome Res.

160

155

View full text Add to dashboard Cite

show abstract

“…Aerobic and anaerobic exercise forearm tests display no increase in lactate values (lactate flat response) (Kazemi-Stephani et al 2002). Molecular heterogeneity has been demonstrated by the identification of various different mutations in the coding regions or splice sites of the gene , Bartram et al 1993, Bruno et al 1999a, Bruno et al 1999b, Bruno et al 2006, Deschauer et al 2003, Fernandez-Cadenas et al 2003, Martin et al 2001a, Martin et al 2001b, Quintans et al 2004, Tsujino et al 1994a, Tsujino et al 1993, Tsujino et al 1994b, Vorgerd et al 1998. The most common among European and American patients is a nonsense mutation at codon 50 in exon 1 (p.R50X) (Andreu et al 1998, Bartram et al 1993, Bruno et al 2006, el-Schahawi et al 1996, Martin et al 2001a, Martinuzzi et al 1996, Tsujino et al 1993, Tsujino et al 1995, Vorgerd et al 1998.…”

mentioning

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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“…Therefore, the R193W mutation would presumably affect glucose-6-P binding and allosteric control of MPL. Of the 17 mutations in the PYGM gene identified so far (Tsujino et al, 1995;Vogerd et al, 1998;Bruno et al, 1999), only the missense mutation L291P (Tsujino et al, 1994) disrupts dimer contact pairs belonging to a further network, the so-called tower helix and gate loop, which is involved in the allosteric control of the active site.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic defects of the myophosphorylase gene (PYGM) cause a typical metabolic myopathy (McArdle´s disease) (MIM# 232600) characterized by exercise intolerance, premature fatigue, myalgia, muscle cramps and recurrent myoglobinuria (DiMauro and Tsujino, 1994). Molecular heterogeneity has been demonstrated by the identification of various different mutations in the coding regions or splice sites of the gene (Tsujino et al, 1995;Vogerd et al, 1998;Andreu et al, 1999;Bruno et al, 1999). The most common among European and American patients is a nonsense mutation at codon 49 in exon 1 (R49X) (Tsujino et al, 1993;Martinuzzi et al, 1996;Andreu et al, 1998;Vogerd et al, 1998).…”

Section: Introductionmentioning

confidence: 99%