Association of a Novel ACTA1 Mutation With a Dominant Progressive Scapuloperoneal Myopathy in an Extended Family.
OBJECTIVE
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.


METHODS
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.


METHODS
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
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.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Kristen
K
Zukosky
National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland.
Katherine
K
Meilleur
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Bryan J
BJ
Traynor
Division of Child Neurology, Columbia University Medical Center, New York, New York.
Jahannaz
J
Dastgir
Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Livija
L
Medne
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.
Marcella
M
Devoto
Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
James
J
Collins
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland11Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC.
Jachinta
J
Rooney
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Yaqun
Y
Zou
Department of Pediatrics and Neurology, Children's Hospital Colorado, Aurora.
Michele L
ML
Yang
Computational Biology Core, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
J Raphael
JR
Gibbs
Department of Chemistry, Microbiology, Biochemistry, and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Markus
M
Meier
Department of Chemistry, Microbiology, Biochemistry, and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Joerg
J
Stetefeld
Department of Pediatrics, Nemours Children's Hospital, Orlando, Florida.
Richard S
RS
Finkel
Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximillans University of Munich, Munich, Germany.
Joachim
J
Schessl
Department of Neurology, University of Pennsylvania, Philadelphia.
Lauren
L
Elman
Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, Connecticut.
Kevin
K
Felice
Shriners Pediatric Research Center, Department of Neurology, Temple University, Philadelphia, Pennsylvania.
Toby A
TA
Ferguson
The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Ozge
O
Ceyhan-Birsoy
The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Alan H
AH
Beggs
Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Gihan
G
Tennekoon
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Janel O
JO
Johnson
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Carsten G
CG
Bönnemann
D000199:Actins / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D002648:Child; D018450:Disease Progression; D059472:Exome / Q000235:genetics; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D020125:Mutation, Missense / Q000235:genetics; D017696:Myopathies, Nemaline; D010375:Pedigree; D010641:Phenotype
D000199:Actins