A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin.
Desminopathy is a familial or sporadic cardiac and skeletal muscular dystrophy associated with mutations in desmin. We have previously characterized a de novo desmin R406W mutation in a patient of European origin with early onset muscle weakness in the lower extremities and atrioventricular conduction block requiring a permanent pacemaker. The disease relentlessly progressed resulting in severe incapacity within 5 years after onset. We have now identified three other patients with early onset rapidly progressive cardiac and skeletal myopathy caused by this same desmin R406W mutation. The mutation was present in each studied patient, but not in their parents or other unaffected family members, indicating that the mutation in all four cases was generated de novo. The patients' mutation-carrying chromosomes showed no similarity, suggesting that the R406W mutation has occurred independently. These observations strongly confirm that the de novo R406W desmin mutation is the genetic basis for early-onset cardiac and skeletal myopathy in patients with sporadic disease and indicate that desmin position 406 is a hot spot for spontaneous mutations. The high pathogenic potential of this mutation can be explained by its location in the highly conserved YRKLLEGEE motif at the C-terminal end of the 2B helix that has a critical role in the process of desmin filament assembly.
Dagvadorj
Ayush
A
National Institute of Neurological Disorders and Stroke, National Institutes of Health Bldg 10, Room 4B37, 10 Center Dr., MSC 1361, Bethesda, Maryland 20892-1361, USA.
Olivé
Montse
M
Urtizberea
Jean-Andoni
JA
Halle
Martin
M
Shatunov
Alexey
A
Bönnemann
Carsten
C
Park
Kye-Yoon
KY
Goebel
Hans H
HH
Ferrer
Isidro
I
Vicart
Patrick
P
Dalakas
Marinos C
MC
Goldfarb
Lev G
LG
D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution; D001483:Base Sequence / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D017124:Conserved Sequence; D003893:Desmin / Q000235:genetics*; D018450:Disease Progression; D005060:Europe; D005260:Female; D006327:Heart Block / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D008958:Models, Molecular; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000473:pathology*; D010375:Pedigree; D017433:Protein Structure, Secondary / Q000235:genetics
D003893:Desmin