title: A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia.
abstract: BACKGROUND
  Protein aggregate myopathies are increasingly recognised conditions characterised by a surplus of endogenous proteins. The molecular and mutational background for many protein aggregate myopathies has been clarified with the discovery of several underlying mutations. Familial idiopathic hyperCKaemia is a benign genetically heterogeneous condition with autosomal dominant features in a high proportion of cases.
  
  
  METHODS
  In 10 patients from three Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia, we performed linkage analysis and exome sequencing as well as morphological and biochemical investigations.
  
  
  CONCLUSIONS
  We show, by Sanger and exome sequencing, that the protein aggregate myopathy with benign evolution and muscle inclusions composed of excess CASQ1, affecting three Italian families, is due to the D244G heterozygous missense mutation in the CASQ1 gene. Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect. Results from immunocytochemistry, electron microscopy, biochemistry and transfected cell line investigations contribute to our understanding of pathogenetic mechanisms underlining this defect. The mutation is common to other Italian patients and is likely to share a founder effect with them. HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation. It is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed, and the condition could be more common than supposed.
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Blasi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sansanelli
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ruggieri
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milano, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Moriggi
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milano, Italy CNR-Institute of Bioimaging and Molecular Physiology, Milano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Vasso
authors.affiliation: Medical Genetics, University of Trieste, Trieste, Italy.
authors.forename: Adamo Pio
authors.initials: AP
authors.lastname: D'Adamo
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Blasevich
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Zanotti
authors.affiliation: CeSI, Center for Research on Ageing & Department of Neuroscience, Imaging, and Clinical Sciences, University G D'Annunzio of Chieti, Chieti, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Paolini
authors.affiliation: CeSI, Center for Research on Ageing & Department of Neuroscience, Imaging, and Clinical Sciences, University G D'Annunzio of Chieti, Chieti, Italy.
authors.forename: Feliciano
authors.initials: F
authors.lastname: Protasi
authors.affiliation: Neurology Unit, F Tappeiner Hospital of Merano, Merano, Italy.
authors.forename: Frediano
authors.initials: F
authors.lastname: Tezzon
authors.affiliation: Department of Biomedical Sciences for Health, University of Milano, Milano, Italy CNR-Institute of Bioimaging and Molecular Physiology, Milano, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gelfi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Faculty of Medicine, Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS Neurological Institute C. Besta, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002155:Calsequestrin; D002460:Cell Line; D003241:Consanguinity; D006801:Humans; D007558:Italy; D016464:Lysosomal Storage Diseases / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D066263:Protein Aggregation, Pathological; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: C503129:CASQ1 protein, human; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D024101:Mitochondrial Proteins
keywords: Clinical genetics; Genome-wide; Molecular genetics; Neuromuscular disease