OBJECTIVE: To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles. METHODS: Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6. RESULTS: Exome analysis in 3 affected individuals from a family with dominant LGMD and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself. INTERPRETATION: Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.
OBJECTIVE: To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles. METHODS: Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6. RESULTS: Exome analysis in 3 affected individuals from a family with dominant LGMD and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself. INTERPRETATION: Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.
Authors: Rodrigo A Fuentealba; Maria Udan; Shaughn Bell; Iga Wegorzewska; Jieya Shao; Marc I Diamond; Conrad C Weihl; Robert H Baloh Journal: J Biol Chem Date: 2010-06-16 Impact factor: 5.157
Authors: C Coutton; B Poreau; F Devillard; C Durand; S Odent; C Rozel; G Vieville; F Amblard; P-S Jouk; V Satre Journal: Mol Syndromol Date: 2013-10-02
Authors: Sandra Donkervoort; Carl E Kutzner; Ying Hu; Xavière Lornage; John Rendu; Tanya Stojkovic; Jonathan Baets; Sarah B Neuhaus; Jantima Tanboon; Reza Maroofian; Véronique Bolduc; Magdalena Mroczek; Stefan Conijn; Nancy L Kuntz; Ana Töpf; Soledad Monges; Fabiana Lubieniecki; Riley M McCarty; Katherine R Chao; Serena Governali; Johann Böhm; Kanokwan Boonyapisit; Edoardo Malfatti; Tumtip Sangruchi; Iren Horkayne-Szakaly; Carola Hedberg-Oldfors; Stephanie Efthymiou; Satoru Noguchi; Sarah Djeddi; Aritoshi Iida; Gabriella di Rosa; Chiara Fiorillo; Vincenzo Salpietro; Niklas Darin; Julien Fauré; Henry Houlden; Anders Oldfors; Ichizo Nishino; Willem de Ridder; Volker Straub; Wojciech Pokrzywa; Jocelyn Laporte; A Reghan Foley; Norma B Romero; Coen Ottenheijm; Thorsten Hoppe; Carsten G Bönnemann Journal: Am J Hum Genet Date: 2020-11-19 Impact factor: 11.025
Authors: Claudia Gonzaga-Jauregui; Tamar Harel; Tomasz Gambin; Maria Kousi; Laurie B Griffin; Ludmila Francescatto; Burcak Ozes; Ender Karaca; Shalini N Jhangiani; Matthew N Bainbridge; Kim S Lawson; Davut Pehlivan; Yuji Okamoto; Marjorie Withers; Pedro Mancias; Anne Slavotinek; Pamela J Reitnauer; Meryem T Goksungur; Michael Shy; Thomas O Crawford; Michel Koenig; Jason Willer; Brittany N Flores; Igor Pediaditrakis; Onder Us; Wojciech Wiszniewski; Yesim Parman; Anthony Antonellis; Donna M Muzny; Nicholas Katsanis; Esra Battaloglu; Eric Boerwinkle; Richard A Gibbs; James R Lupski Journal: Cell Rep Date: 2015-08-06 Impact factor: 9.423
Authors: Songqing Li; Peipei Zhang; Brian D Freibaum; Nam Chul Kim; Regina-Maria Kolaitis; Amandine Molliex; Anderson P Kanagaraj; Ichiro Yabe; Mishie Tanino; Shinya Tanaka; Hidenao Sasaki; Eric D Ross; J Paul Taylor; Hong Joo Kim Journal: Hum Mol Genet Date: 2016-01-06 Impact factor: 6.150