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Link to original content: http://omim.org/entry/180903
Alternative titles; symbols
HGNC Approved Gene Symbol: RYR3
Cytogenetic location: 15q13.3-q14 Genomic coordinates (GRCh38) : 15:33,310,967-33,866,102 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q13.3-q14 | Congenital myopathy 20 | 620310 | Autosomal recessive | 3 |
The RYR3 gene encodes ryanodine receptor-3, which is a member of a family of intracellular calcium ion release channels responsible for the release of Ca(2+) from intracellular stores following stimulation. The RYR3 gene is expressed in skeletal muscle and brain (summary by Nilipour et al., 2018).
Hakamata et al. (1992) deduced the complete amino acid sequence of a novel ryanodine receptor/calcium release channel from rabbit brain by cloning and sequence analysis of the cDNA. The protein was composed of 4,872 amino acids and shared characteristic structural features with the skeletal muscle (RYR1; 180901) and cardiac (RYR2; 180902) ryanodine receptors. RNA blot hybridization analysis showed that the brain ryanodine receptor is abundantly expressed in corpus striatum, thalamus, and hippocampus, whereas the cardiac ryanodine receptor is more uniformly expressed in the brain. The brain ryanodine receptor gene was also transcribed in smooth muscle.
Using rabbit Ryr3 cDNA as probe, Nakashima et al. (1997) cloned RYR3 from a brain cDNA library. The deduced 4,866-amino acid protein has a calculated molecular mass of about 551 kD. RYR3 contains 4 repeated sequences organized into 2 tandem pairs, as well as 4 highly hydrophobic C-terminal segments. It does not have an N-terminal signal sequence. Northern blot analysis detected a 16-kb transcript expressed at high levels in caudate nucleus, amygdala, and hippocampus, and at lower levels in corpus callosum, substantia nigra, and thalamus. Abundant expression was also detected in skeletal muscle, and a faint signal was detected in heart.
Leeb and Brenig (1998) isolated overlapping human RYR3 clones from a random primed fetal brain cDNA library. The gene encodes a 4,870-amino acid polypeptide that contains 4 RYR repeats, 3 SPRY domains, an ATP/GTP binding site consensus sequence, and 3 potential calmodulin-binding sites. They identified an alternatively spliced transcript that encodes a truncated protein.
Jiang et al. (2003) identified 7 alternatively spliced variants of rabbit Ryr3 that were expressed in a tissue-specific manner.
Nilipour et al. (2018) found expression of RYR3 in control fetal and adult human skeletal muscle and brain tissue. The immunostaining pattern in myofibers was slightly different than that of RYR1, suggesting distinct roles for the 2 channels in muscle tissue.
By functional expression of RYR3 and a chimeric RYR, Nakashima et al. (1997) confirmed that RYR3 forms a calcium release channel with low Ca(2+) sensitivity.
Jiang et al. (2003) characterized several rabbit Ryr3 splice variants. One variant lacked a predicted transmembrane helix encoded by exon 92 and was highly expressed in smooth muscle tissues, but not in skeletal muscle, heart, or brain. This variant did not form a functional Ca(2+) channel when expressed alone in HEK293 cells, but it formed functional heteromeric channels with reduced caffeine sensitivity when coexpressed with wildtype Ryr3. This variant was also able to form heteromeric channels with and suppress the activity of Ryr2 in a dominant-negative manner. Jiang et al. (2003) concluded that the heterogeneity of Ryr3 splice variants may explain the unique tissue-specific pharmacologic and functional properties of Ryr3.
By isotopic in situ hybridization, Sorrentino et al. (1993) mapped the RYR3 gene to 15q14-q15; 15q15 is a probable location. By in situ hybridization, Mattei et al. (1994) mapped the type 3 ryanodine receptor to mouse chromosome 2E5-2F3. Richard et al. (1994) presented an integrated physical, expression, and genetic map of chromosome 15. They found that the RYR3 gene fell in their region I: 15pter-q14.
In a 22-year-old woman with congenital myopathy-20 (CMYO20; 620310), Nilipour et al. (2018) identified compound heterozygous missense mutations in the RYR3 gene (M2070V, 180903.0001 and R2980L, 180903.0002). The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were found at a low frequency in the gnomAD database in the heterozygous state. Functional studies of the variants were not performed.
In 2 unrelated children with CMYO20 presenting as arthrogryposis, Pehlivan et al. (2019) identified homozygous or compound heterozygous mutations in the RYR3 gene (180902.0002-180902.0004). These 2 patients were ascertained from a cohort of 89 families with arthrogryposis who underwent exome sequencing. The study also found another patient, born of consanguineous Turkish parents, with arthrogryposis associated with biallelic likely pathogenic mutations in 2 genes: RYR3 and MYO18B (607295), consistent with a multilocus etiology. Functional studies of the variants were not performed, but Pehlivan et al. (2019) noted the role of RYR3 in calcium signaling and release, consistent with a role in neuromuscular disease.
Pergande et al. (2020) identified a heterozygous missense variant in the RYR3 gene (D4605G) in a fetus (case 45) with fetal akinesia. The patient was part of a cohort of 51 patients with fetal akinesia who underwent next-generation sequencing. Functional studies of the RYR3 variant were not performed. After termination of the pregnancy, the affected fetus was found to have contractures, scoliosis, ventricular septal defect, intestinal malrotation, and elbow joint pterygia.
Takeshima et al. (1996), Bertocchini et al. (1997), and Futatsugi et al. (1999) independently generated Ryr3-deficient mice. In all cases, the homozygous mutant mice were fertile and displayed no gross abnormalities. Takeshima et al. (1996) detected increased locomotor activity in Ryr3 knockout mice compared to that of the control mice and concluded that the lack of Ryr3-mediated Ca(2+) signaling results in abnormalities of certain neurons in the central nervous system.
Bertocchini et al. (1997) detected normal Ryr3 expression in murine skeletal muscles during the postnatal phase of muscle development, but not in muscles of adult mice, with the exception of the diaphragm and soleus muscles. The authors demonstrated that skeletal muscle contraction in Ryr3 knockout mice was impaired during the first weeks after birth. They concluded that Ryr3 has a physiologic role in excitation-contraction coupling of neonatal skeletal muscles.
Futatsugi et al. (1999) measured the electrophysiologic and pharmacologic properties of synaptic plasticity in the CA1 area of Ryr3-deficient mice. The results suggested that Ryr3-mediated intracellular calcium release from endoplasmic reticulum may inhibit hippocampal long-term potentiation (LTP) and spatial learning.
Barone et al. (1998) generated double mutant mice carrying a targeted disruption of both the Ryr1 and Ryr3 genes. Skeletal muscles from mice homozygous for both mutations did not contract in response to caffeine or ryanodine. In addition, these muscles showed very low tension when directly activated with micromolar ionized calcium after membrane permeabilization, indicating either poor development or degeneration of the myofibrils. This was confirmed by biochemical analysis of contractile proteins. Electron microscopy confirmed small size of myofibrils and showed complete absence of feet (RyRs) in the junctional sarcoplasmic reticulum.
Balschun et al. (1999) found that hippocampal tissue from Ryr3 knockout mice showed no morphologic changes and had robust in vitro LTP induced by repeated strong tetanization in the CA1 region, similar to control tissue. However, the hippocampal tissue from the mutant mice showed significantly impaired initial amplitude of potentiation and LTP maintenance in response to weak tetanization compared to controls. In a water maze test, the mutant animals showed normal learning acquisition but had deficits in spatial learning, suggesting impaired synaptic plasticity. Balschun et al. (1999) concluded that RYR3 has a functional role in hippocampal synaptic plasticity, specifically on the adaptation of acquired memory in response to external changes or stimuli.
In a 22-year-old woman with congenital myopathy-20 (CMYO20; 620310), Nilipour et al. (2018) identified compound heterozygous missense variants in the RYR3 gene: a c.6208A-G transition in exon 40, resulting in a met2070-to-val (M2070V) substitution, and a c.8939G-T transversion in exon 63, resulting in an arg2980-to-leu (R2980L; 180903.0002) substitution. The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both variants were found at a low frequency in the gnomAD database in the heterozygous state. Functional studies of the variants were not performed. After normal early development, the patient developed muscle weakness manifest as difficulty running and climbing stairs around 5 years of age. She had a positive Gowers sign and mild weakness of the arms. At age 22, she had mild proximal muscle weakness in all 4 limbs and mild scapular winging, but no scoliosis. She also had a long narrow face, high-arched palate, facial weakness, and micrognathia, but no ophthalmoplegia or ptosis. Serum creatine kinase was normal and EMG showed a myopathic pattern. Skeletal muscle biopsy showed wide variation in fiber size with type 1 fiber predominance and atrophy, hypertrophic type 2 fibers, increased internal nuclei, and abundant nemaline bodies in the perinuclear and subsarcolemmal areas, as well as in the cytoplasm. There were some core-like regions as well. Mutations in known nemaline myopathy-associated genes were excluded.
For discussion of the c.8939G-T transversion in exon 63 of the RYR3 gene, resulting in an arg2980-to-leu (R2980L) substitution, that was found in compound heterozygous state in a patient with congenital myopathy-20 (CMYO20; 620310) by Nilipour et al. (2018), see 180903.0001.
In a 15-year-old girl (BAB8988), born of consanguineous parents (family HOU3274), with CMYO20 presenting as arthrogryposis, Pehlivan et al. (2019) identified a homozygous R2980L (c.8939G-T, NM_001243996) mutation in the RYR3 gene that segregated with the disorder in the family. Functional studies of the variant were not performed. The mutation was present in 19 individuals in gnomAD in the heterozygous state.
In a 3-year-old girl (PAED187) with congenital myopathy-20 (CMYO20; 620310) presenting as arthrogryposis, Pehlivan et al. (2019) identified compound heterozygous mutations in the RYR3 gene: a c.2000A-G transition (c.2000A-G, NM_001036.3), resulting in an asp667-to-gly (D667G) substitution, and an intronic G-to-A transition (c.11164+1G-A; 180903.0004), predicted to result in a splicing defect. The mutations, which were found by exome sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed. In addition to contractures, this patient had global developmental delay and dysmorphic facies.
For discussion of the intronic G-to-A transition (c.11164+1G-A, NM_001036.3) in exon 83 of the RYR3 gene, predicted to result in a splicing defect, that was found in compound heterozygous state in a patient with congenital myopathy-20 (CMYO20; 620310) by Pehlivan et al. (2019), see 180903.0003.
Balschun, D., Wolfer, D. P., Bertocchini, F., Barone, V., Conti, A., Zuschratter, W., Missiaen, L., Lipp, H.-P., Frey, J. U., Sorrentino, V. Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning. EMBO J. 18: 5264-5273, 1999. [PubMed: 10508160] [Full Text: https://doi.org/10.1093/emboj/18.19.5264]
Barone, V., Bertocchini, F., Bottinelli, R., Protasi, F., Allen, P. D., Armstrong, C. F., Reggiani, C., Sorrentino, V. Contractile impairment and structural alterations of skeletal muscles from knockout mice lacking type 1 and type 3 ryanodine receptors. FEBS Lett. 422: 160-164, 1998. [PubMed: 9489997] [Full Text: https://doi.org/10.1016/s0014-5793(98)00003-9]
Bertocchini, F., Ovitt, C. E., Conti, A., Barone, V., Scholer, H. R., Bottinelli, R., Reggiani, C., Sorrentino, V. Requirement for the ryanodine receptor type 3 for efficient contraction in neonatal skeletal muscles. EMBO J. 16: 6956-6963, 1997. [PubMed: 9384575] [Full Text: https://doi.org/10.1093/emboj/16.23.6956]
Futatsugi, A., Kato, K., Ogura, H., Li, S.-T., Nagata, E., Kuwajima, G., Tanaka, K., Itohara, S., Mikoshiba, K. Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking ryanodine receptor type 3. Neuron 24: 701-713, 1999. [PubMed: 10595520] [Full Text: https://doi.org/10.1016/s0896-6273(00)81123-x]
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