Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies

Y. Nilipour, S. Nafissi, A. E. Tjust, G. Ravenscroft, H. Hossein Nejad Nedai, R. L. Taylor, V. Varasteh, F. Pedrosa Domellöf, M. Zangi, S. H. Tonekaboni, M. Olivé, K. Kiiski, L. Sagath, M. R. Davis, N. G. Laing, H. Tajsharghi

Research output: Contribution to journalArticle

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Abstract

Background and purpose: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. Methods and results: Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next-generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina samples. Immunofluorescence of human skeletal muscle revealed a ‘single-row’ appearance of RYR3, interspersed between the ‘double rows’ of ryanodine receptor type 1 (RYR1) at each A–I junction. Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

Original languageEnglish
Pages (from-to)841-847
Number of pages7
JournalEuropean Journal of Neurology
Volume25
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

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Nemaline Myopathies
Ryanodine Receptor Calcium Release Channel
Genes
Skeletal Muscle
Mutation
Cauda Equina
Muscles
Comparative Genomic Hybridization
Palate
Brain
Scoliosis
Atrophy
Fluorescent Antibody Technique
Cytoplasm
Extremities

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Nilipour, Y. ; Nafissi, S. ; Tjust, A. E. ; Ravenscroft, G. ; Hossein Nejad Nedai, H. ; Taylor, R. L. ; Varasteh, V. ; Pedrosa Domellöf, F. ; Zangi, M. ; Tonekaboni, S. H. ; Olivé, M. ; Kiiski, K. ; Sagath, L. ; Davis, M. R. ; Laing, N. G. ; Tajsharghi, H. / Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies. In: European Journal of Neurology. 2018 ; Vol. 25, No. 6. pp. 841-847.
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abstract = "Background and purpose: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. Methods and results: Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next-generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina samples. Immunofluorescence of human skeletal muscle revealed a ‘single-row’ appearance of RYR3, interspersed between the ‘double rows’ of ryanodine receptor type 1 (RYR1) at each A–I junction. Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.",
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author = "Y. Nilipour and S. Nafissi and Tjust, {A. E.} and G. Ravenscroft and {Hossein Nejad Nedai}, H. and Taylor, {R. L.} and V. Varasteh and {Pedrosa Domell{\"o}f}, F. and M. Zangi and Tonekaboni, {S. H.} and M. Oliv{\'e} and K. Kiiski and L. Sagath and Davis, {M. R.} and Laing, {N. G.} and H. Tajsharghi",
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Nilipour, Y, Nafissi, S, Tjust, AE, Ravenscroft, G, Hossein Nejad Nedai, H, Taylor, RL, Varasteh, V, Pedrosa Domellöf, F, Zangi, M, Tonekaboni, SH, Olivé, M, Kiiski, K, Sagath, L, Davis, MR, Laing, NG & Tajsharghi, H 2018, 'Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies' European Journal of Neurology, vol. 25, no. 6, pp. 841-847. https://doi.org/10.1111/ene.13607

Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies. / Nilipour, Y.; Nafissi, S.; Tjust, A. E.; Ravenscroft, G.; Hossein Nejad Nedai, H.; Taylor, R. L.; Varasteh, V.; Pedrosa Domellöf, F.; Zangi, M.; Tonekaboni, S. H.; Olivé, M.; Kiiski, K.; Sagath, L.; Davis, M. R.; Laing, N. G.; Tajsharghi, H.

In: European Journal of Neurology, Vol. 25, No. 6, 01.06.2018, p. 841-847.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies

AU - Nilipour, Y.

AU - Nafissi, S.

AU - Tjust, A. E.

AU - Ravenscroft, G.

AU - Hossein Nejad Nedai, H.

AU - Taylor, R. L.

AU - Varasteh, V.

AU - Pedrosa Domellöf, F.

AU - Zangi, M.

AU - Tonekaboni, S. H.

AU - Olivé, M.

AU - Kiiski, K.

AU - Sagath, L.

AU - Davis, M. R.

AU - Laing, N. G.

AU - Tajsharghi, H.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background and purpose: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. Methods and results: Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next-generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina samples. Immunofluorescence of human skeletal muscle revealed a ‘single-row’ appearance of RYR3, interspersed between the ‘double rows’ of ryanodine receptor type 1 (RYR1) at each A–I junction. Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

AB - Background and purpose: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. Methods and results: Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next-generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina samples. Immunofluorescence of human skeletal muscle revealed a ‘single-row’ appearance of RYR3, interspersed between the ‘double rows’ of ryanodine receptor type 1 (RYR1) at each A–I junction. Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

KW - intracellular Ca channels

KW - nemaline myopathy

KW - ryanodine receptors

KW - RYR3

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DO - 10.1111/ene.13607

M3 - Article

VL - 25

SP - 841

EP - 847

JO - European Journal of Neurology

JF - European Journal of Neurology

SN - 1351-5101

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