An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor

Abstract

Central core disease (CCD) and nemaline myopathy (NM) are congenital myopathies for which differential diagnosis is often based on the presence either of cores or rods. Missense mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in some families with CCD. Mutations in the alpha-tropomyosin and alpha-actin genes have been associated with most dominant forms of NM. Analysis of the RYR1 cDNA in a French family identified a novel Y4796C mutation that lies in the C-terminal channel-forming domain of the RyR1 protein. This mutation was linked not only to a severe and penetrant form of CCD, but also to the presence of rods in the muscle fibres and to the malignant hyperthermia susceptibility (MHS) phenotype. The Y4796C mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. Expression of the mutant RYR1 cDNA produced channels with increased caffeine sensitivity and a significantly reduced maximal level of Ca(2+) release. Single-cell Ca(2+) analysis showed that the resting cytoplasmic level was increased by 60% in cells expressing the mutant channel. These data support the view that the rate of Ca(2+) leakage is increased in the mutant channel. The resulting chronic elevation in myoplasmic concentration is likely to be responsible for the severe expression of the disease. Haplotyping analysis indicated that the mutation arose as a neomutation in the proband. This first report of a neomutation in the RYR1 gene has strong implications for genetic linkage studies of MHS or CCD, two diseases characterized by a genetic heterogeneity.

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

“…The majority of RyR1 mutations linked to MH cluster in the cytoplasmic domains of RyR1 (amino acids 35 to 614 and 2129 to 2458). Another cluster of mutations is found near the carboxyl terminus (4637 to 4973) (Phillips et al 1994;Quane et al 1994;Lynch et al 1999;Monnier et al 2000;Scacheri et al 2000;Tilgen et al 2001). MH is often a silent disorder that goes undetected until the patient undergoes surgery or is exposed to high ambient temperatures ( 378C) (JurkatRoth et al 2000).…”

Clinical utility gene card for: Central core disease

“…Histopathological features: Typical RYR1-related CCD is characterised by well-defined, single or multiple, central or eccentric cores running a significant extent along the longitudinal muscle fibre axis on muscle biopsy. 14 In cases with suggestive clinical features but less specific histopathological findings such as type 1 predominance, uniformity, 15 or cores and rods, 16,17 muscle MRI may be more indicative of RYR1 involvement than muscle biopsy (see below). Muscle MR imaging: Muscle MR imaging in RYR1-related CCD shows a characteristic and consistent pattern of selective involvement, which may aid genetic testing and distinguish from core myopathies with different genetic backgrounds.…”

“…Combination of central cores and nemaline rods in particular may also be seen with certain RYR1 mutations. 16,17 2.4 Clinical specificity (proportion of negative tests if the disease is not present) No precise data regarding the clinical specificity of RYR1 testing in CCD are currently available, however, clinical specificity is likely to be o100% considering the large number of sequence variations of uncertain significance identified in the RYR1 gene. In most cases, a detailed clinical assessment and muscle biopsy will have been performed before genetic testing; therefore, presence of the condition is a prerequisite for the initiation of genetic testing but also of importance for the interpretation of RYR1 variations of uncertain significance.…”

Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

“…To exclude from the search for a seventh NM gene in those Turkish families that might have a mutation in a known NM gene, we analysed the families for linkage to the known NM gene loci, and also to the mixed core-rod myopathy ryanodine receptor (RYR1) (OMIM 180901) locus on chromosome 19, 10,11 and to the core-rod locus on chromosome 15. 12 In the chromosomal region 1q12-21.2 where TPM3 is located, we analysed eight microsatellite markers encompassing a region of 18 cM; D1S252, D1S498, D1S2347, D1S2858, D1S305, D1S2624, D1S2635, and D1S484.…”