Kristen Zukosky1, Katherine Meilleur2, Bryan J Traynor3, Jahannaz Dastgir4, Livija Medne5, Marcella Devoto6, James Collins7, Jachinta Rooney8, Yaqun Zou1, Michele L Yang9, J Raphael Gibbs10, Markus Meier11, Joerg Stetefeld11, Richard S Finkel12, Joachim Schessl13, Lauren Elman14, Kevin Felice15, Toby A Ferguson16, Ozge Ceyhan-Birsoy17, Alan H Beggs17, Gihan Tennekoon5, Janel O Johnson3, Carsten G Bönnemann1. 1. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. 2. National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland. 3. Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. 4. Division of Child Neurology, Columbia University Medical Center, New York, New York. 5. Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 6. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia7Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia8Department of Molecular Medicine, Universit. 7. Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 8. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland11Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC. 9. Department of Pediatrics and Neurology, Children's Hospital Colorado, Aurora. 10. Computational Biology Core, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. 11. Department of Chemistry, Microbiology, Biochemistry, and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. 12. Department of Pediatrics, Nemours Children's Hospital, Orlando, Florida. 13. Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximillans University of Munich, Munich, Germany. 14. Department of Neurology, University of Pennsylvania, Philadelphia. 15. Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, Connecticut. 16. Shriners Pediatric Research Center, Department of Neurology, Temple University, Philadelphia, Pennsylvania. 17. The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract
IMPORTANCE: New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene. OBJECTIVE: To determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing. DESIGN, SETTING, AND PARTICIPANTS: Fourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions. MAIN OUTCOMES AND MEASURES: Examination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7). RESULTS: Clinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1. The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals. CONCLUSIONS AND RELEVANCE: This family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.
IMPORTANCE: New genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene. OBJECTIVE: To determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing. DESIGN, SETTING, AND PARTICIPANTS: Fourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions. MAIN OUTCOMES AND MEASURES: Examination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7). RESULTS: Clinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1. The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals. CONCLUSIONS AND RELEVANCE: This family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.
Authors: S T Sherry; M H Ward; M Kholodov; J Baker; L Phan; E M Smigielski; K Sirotkin Journal: Nucleic Acids Res Date: 2001-01-01 Impact factor: 16.971
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Authors: B Ilkovski; S T Cooper; K Nowak; M M Ryan; N Yang; C Schnell; H J Durling; L G Roddick; I Wilkinson; A J Kornberg; K J Collins; G Wallace; P Gunning; E C Hardeman; N G Laing; K N North Journal: Am J Hum Genet Date: 2001-04-27 Impact factor: 11.025
Authors: H Jungbluth; C A Sewry; S C Brown; K J Nowak; N G Laing; C Wallgren-Pettersson; K Pelin; A Y Manzur; E Mercuri; V Dubowitz; F Muntoni Journal: Neuromuscul Disord Date: 2001-01 Impact factor: 4.296
Authors: Nigel G Laing; Nigel F Clarke; Danielle E Dye; Khema Liyanage; Kendall R Walker; Yasuaki Kobayashi; Shuichi Shimakawa; Tohru Hagiwara; Robert Ouvrier; John C Sparrow; Ichizo Nishino; Kathryn N North; Ikuya Nonaka Journal: Ann Neurol Date: 2004-11 Impact factor: 10.422