Brody Disease: Insights Into Biochemical Features of SERCA1 and Identification of a Novel Mutation

Abstract

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.

Brody syndrome: A clinically heterogeneous entity distinct from Brody disease

“…This was done on transverse muscle sections using fluorescence method with antibodies to SERCA1 (1:500; Santa Cruz Biotechnology, Santa Cruz, CA) and SERCA2 (1:100; Santa Cruz Biotechnology, Santa Cruz, CA). We compared the results with controls including biopsies of vastus lateralis muscle from subjects who were found to be free of muscle disease [14,19].…”

“…We reviewed all publications cited by Pubmed on 'Brody disease', 'Brody syndrome' or 'Brody myopathy' since the initial description in 1969 by Brody [2] until 2010 and the references of these articles, and selected all patients in whom clinical data were available (n = 32; Supplementary Table 1) [2,4,5,[7][8][9][10][11][12][13][14]. We classified them as literature ("L") cases, numbered them chronologically, and screened the case descriptions for clinical key features of Brody disease.…”

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

“…Functional studies on muscle samples from humans with Brody's disease have demonstrated that some patients exhibit reduced levels of SERCA1 protein content [105,106], while in other cases the levels of SERCA1 protein are unaltered, but there is a significant reduction (up to 80%) in the Ca 2+ pumping activity both in homogenates of muscle samples and in myotubes explanted from patients [99,106,107]. Chianina cattle pseudomyotonia, a disease similar to Brody's disease affecting cattle, is caused by the homozygous ATP2A1 p.R164H mutation [108].…”

Transfection efficiency in rat soleus and SERCA1b expression in human skeletal muscles

“…Five of these patients (BD2 and BS2-BS5) have been previously described at clinical, morphological, biochemical and genetic level; one (BD2) was a compound heterozygous with two in-frame deletions occurring in exon 3 (Leu65) and in exon 15 (Glu606) of ATP2A1 [12] while in the remaining four patients (BS2-BS5) no pathogenic mutations were detected in the gene (S3, S2, S8 and S5 in Voermans et al [7]). …”

“…Ultrastructural abnormalities include increased number of membranous bodies within sarcoplasmic reticulum (SR) vesicles, enlargement of lateral cisternae with proliferation of the tubular SR elements and presence of swollen mitochondria [11,12].…”