Genotype-phenotype correlations in recessive RYR1-related myopathies

Orphanet Journal of Rare Diseases

James J Dowling¹  Nigel F Clarke⁴  Brian Callaghan⁸  Gregory P Wellman²  Jasper R Daube³  James Collins⁷  Katherine D Mathews^1,10  Livija Medne⁵  Carsten G Bonnemann⁹  Mark A Tarnopolsky⁶  Jean H Hwang⁴  Angela Bailey¹  Kimberly Amburgey¹ 

[1] Department of Pediatrics, Taubman Medical Research Institute, University of Michigan Medical Center, 5019 A. Alfred Taubman Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA;The Delta Pathology Group, Shreveport, LA, USA;Department of Neurology, Mayo Foundation for Medical Education and Research, Rochester, MN, USA;Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, University of Sydney, Level 3, Research Building Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia;Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Department of Neuromuscular and Neurometabolic Disease, McMaster University Medical Center, Hamilton, Ontario, Canada;Department of Pediatric Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI, USA;Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD, USA;Departments of Pediatrics and Neurology, University of Iowa, Carver College of Medicine, Iowa City, IA, USA

关键词: Congenital myopathies;    RYR1;    Genotype-phenotype relationships;   

Others  :  863622
DOI  :  10.1186/1750-1172-8-117

 received in 2013-03-06, accepted in 2013-08-01,  发布年份 2013

【 摘 要 】

Background

RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.

Methods

In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases.

Results

Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.

Conclusions

These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.

【 授权许可】

   
2013 Amburgey et al.; licensee BioMed Central Ltd.

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