Journal article
STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.
- Abstract:
- SH3 and cysteine‐rich domain‐containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation–contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997‐1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)‐like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl‐induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co‐immunoprecipitation of STAC3 with CaV1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH‐like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV1.1 sarcolemma mislocalization or impaired STAC3‐CaV1.1 interaction.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Accepted manuscript, 2.3MB, Terms of use)
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- Publisher copy:
- 10.1002/humu.23635
Authors
- Publisher:
- Wiley
- Journal:
- Human Mutation More from this journal
- Volume:
- 39
- Issue:
- 12
- Pages:
- 1980-1994
- Publication date:
- 2018-10-11
- Acceptance date:
- 2018-08-28
- DOI:
- EISSN:
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1098-1004
- ISSN:
-
1059-7794
- Pmid:
-
30168660
- Language:
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English
- Keywords:
- Pubs id:
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1092894
- Local pid:
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pubs:1092894
- Deposit date:
-
2020-03-12
Terms of use
- Copyright holder:
- Wiley
- Copyright date:
- 2018
- Rights statement:
- © 2018 Wiley Periodicals, Inc.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from Wiley at: https://doi.org/10.1002/humu.23635
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