Brody disease: insights into biochemical features of SERCA1 and identification of a novel mutation.
Brody disease is an inherited disorder of skeletal muscle function characterized by increasing impairment of relaxation during exercise. The autosomal recessive form can be caused by mutations in the ATP2A1 gene, which encodes for the sarcoplasmic/endoplasmic reticulum Ca-ATPase 1 (SERCA1) protein. We studied 2 siblings affected by Brody disease. The patients complained of exercise-induced delay of muscle relaxation and stiffness since childhood and had gene analysis of ATP2A1. Morphologic and biochemical studies were performed on a muscle biopsy from 1 patient. The biopsy showed fiber size variation and increased numbers of fibers with internal nuclei. Ultrastructural examination revealed dilatation of lateral cisternae and proliferation of tubular elements of the sarcoplasmic reticulum. By immunohistochemistry, SERCA1 was expressed in a normal pattern, but sarcoplasmic reticulum Ca-ATPase activity was significantly reduced. Immunoblotting after high-resolution 2-dimensional gel electrophoresis showed a significant difference in the amount of SERCA1 protein between the patient and controls. Both patients were found to have 2 previously unreported in-frame deletions in ATP2A1. Because SERCA1 protein has specific biochemical characteristics in our patient, these results underline the importance of a pathologic and biochemical analyses for the diagnosis. In addition, we describe 2 novel mutations in the ATP2A1 gene.
Vattemi
Gaetano
G
Department of Neurological Sciences and Vision, Section of Clinical Neurology, University of Verona, Verona, Italy. gaetano.vattemi@univr.it
Gualandi
Francesca
F
Oosterhof
Arie
A
Marini
Matteo
M
Tonin
Paola
P
Rimessi
Paola
P
Neri
Marcella
M
Guglielmi
Valeria
V
Russignan
Anna
A
Poli
Consuelo
C
van Kuppevelt
Toin H
TH
Ferlini
Alessandra
A
Tomelleri
Giuliano
G
D001706:Biopsy; D020013:Calcium Signaling / Q000235:genetics; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D017079:Exercise Tolerance / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009122:Muscle Hypertonia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D055815:Young Adult
D005819:Genetic Markers; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506943:ATP2A1 protein, human