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Lookup NU author(s): Dr Ana TopfORCiD, Dr Jennifer Duff, Dr Lizzie Harris, Professor Chiara Marini Bettolo, Professor Volker StraubORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© Author(s) (or their employer(s)) 2024.Background Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca2+ homeostasis can contribute to disease pathology. Methods We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples. Results The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum. DNA sequencing identified four unique homozygous loss-of-function variants in JPH1, encoding junctophilin-1 in the four families; one stop-gain (c.354C>A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs*30, c.1738delC;p.Leu580Trpfs*16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. Conclusions Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement.
Author(s): Johari M, Topf A, Folland C, Duff J, Dofash L, Marti P, Robertson T, Vilchez J, Cairns A, Harris E, Marini-Bettolo C, Hundallah K, Alhashem AM, Al-Owain M, Maroofian R, Ravenscroft G, Straub V
Publication type: Article
Publication status: Published
Journal: Journal of Medical Genetics
Year: 2024
Volume: 61
Issue: 10
Pages: 992-998
Print publication date: 01/10/2024
Online publication date: 28/09/2024
Acceptance date: 14/08/2024
Date deposited: 01/10/2024
ISSN (print): 0022-2593
ISSN (electronic): 1468-6244
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/jmg-2024-109970
DOI: 10.1136/jmg-2024-109970
Data Access Statement: Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplementary information. ES and srGS data of probands and family members is available on seqr. All relevant clinical data are shared as part of this study. Identified variants in JPH1 have been submitted to ClinVar with accession numbers SCV004228294-SCV004228296 and SCV004697810. Code for generating plots is available at: https://github.com/RAVING-Informatics/jph1-cm.
PubMed id: 39209426
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