title: Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations?
abstract: BACKGROUND
  Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported.
  
  
  METHODS
  We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation.
  
  
  RESULTS
  The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain-3, suggesting "molecular complementation" in these patients.
  
  
  CONCLUSIONS
  We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain-3, resulting in an exceptionally benign phenotype.
authors: Biodonostia Institute, Hospital Donostia, Po. Dr. Begiristain s/n, 20014 San Sebastián, Basque Country, Spain. amets.saenzpena@osakidetza.net
authors: Amets
authors: A
authors: Sáenz
authors: Yasuko
authors: Y
authors: Ono
authors: Hiroyuki
authors: H
authors: Sorimachi
authors: Maria
authors: M
authors: Goicoechea
authors: France
authors: F
authors: Leturcq
authors: Lorea
authors: L
authors: Blázquez
authors: Federico
authors: F
authors: García-Bragado
authors: Alberto
authors: A
authors: Marina
authors: Juan José
authors: JJ
authors: Poza
authors: Margarita
authors: M
authors: Azpitarte
authors: Naoko
authors: N
authors: Doi
authors: Miguel
authors: M
authors: Urtasun
authors: Jean-Claude
authors: JC
authors: Kaplan
authors: Adolfo
authors: A
authors: López de Munain
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000235:genetics*; D002522:Chlorocebus aethiops; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D009124:Muscle Proteins; C105884:CAPN3 protein, human; D002154:Calpain