title: Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy.
abstract: BACKGROUND
  Protein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.
  
  
  RESULTS
  We detail the mutational, neuropathological, neurophysiological, neurological and radiological features of five new DNAJB6-myopathy families. One has the known Phe93Leu mutation and classic late-onset slowly progressive LGMD1D. Two have different mutations of Phe91 causing a variant childhood-onset severe limb-girdle myopathy. One has a Phe100Val mutation and distal-onset myopathy, unique early bulbar involvement, and a gender-modified wide age-of-onset range. The last has childhood-onset severe distal-onset myopathy and the first non-missense DNAJB6 mutation, c.346 + 5G > A, causing a splicing defect that entirely eliminates DNAJB6's G/F domain (ΔG/F), the domain that harbours all other mutations. Clinical and imaging examinations reveal that muscles considered uninvolved in DNAJB6-myopathy, e.g. lateral gastrocnemii, are affected in our patients with new mutations. Mutational modelling based on the known structure of the bacterial DNAJ2 protein indicates that all past and present mutated residues cluster within 15 Å in the G/F domain and all disturb the interface of this domain with the protein's J domain that confers the interaction with HSP70.
  
  
  CONCLUSIONS
  Our patients expand the phenotypic spectrum of DNAJB6-myopathy and allow tentative genotype-phenotype specifications. Combining with previous studies, the clinical severity spectrum is as follows: ΔG/F and Phe91 mutations, most severe; Phe100, Pro96, Phe89 mutations, intermediate; and Phe93, least severe. As it stands presently, proximal G/F domain mutations (Phe89, Phe91, Phe93) cause proximal limb-girdle myopathy, while distal G/F mutations (Pro96, Phe100) cause distal-onset myopathy. While all mutations affect the G/F-J interaction, each likely does so in different unknown extents or ways. One mutation, ΔG/F, causes its associated severe distal-onset myopathy phenotype in a clear way, through generation of a G/F domain-lacking DNAJB6 protein.
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.|The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ruggieri
authors.affiliation: Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Rome, Italy.|Department of Medical, Oral and Biotechnological Sciences, University of Chieti "G. d'Annunzio", Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Zanotti
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.
authors.forename: Maria Barbara
authors.initials: MB
authors.lastname: Pasanisi
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Saredi
authors.affiliation: Department of Systems Medicine (Neurology), Neuromuscular Disease Unit, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Terracciano
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Antozzi
authors.affiliation: Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Rome, Italy.|Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D Apice
authors.affiliation: Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Rome, Italy.|Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Sangiuolo
authors.affiliation: Medical Genetics Unit, Policlinico Tor Vergata University Hospital, Rome, Italy.|Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.|Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, University of Chieti "G. d'Annunzio", Chieti, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Federici
authors.affiliation: Department of Systems Medicine (Neurology), Neuromuscular Disease Unit, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Massa
authors.affiliation: Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico "C. Besta", Via Celoria 11, 20133, Milan, Italy. marina.mora@istituto-besta.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Canada. berge.minassian@sickkids.ca.|Department of Paediatrics (Neurology) and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Room 6535, 555 University Ave, Toronto, ON, M5G 1X8, Canada. berge.minassian@sickkids.ca.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010649:Phenylalanine / Q000235:genetics; D015898:Tomography Scanners, X-Ray Computed; D014633:Valine / Q000235:genetics; D055815:Young Adult
chemical_list: C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010649:Phenylalanine; D014633:Valine