Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene

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Abstract

The skeletal muscle ryanodine receptor plays a crucial role in excitation–contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca2+ release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

Introduction

The skeletal muscle ryanodine receptor (RYR1) gene on chromosome 19q13.1 encodes the principal sarcoplasmic reticulum (SR) calcium release channel (RyR1), which plays a crucial role in excitation–contraction (EC) coupling by releasing calcium from the SR following muscle activation. RYR1 mutations have been implicated in a wide range of conditions (for review [1]). Among these are malignant hyperthermia susceptibility (MHS) [2] and various congenital myopathies including “core myopathies” with central cores (Central Core Disease, CCD) [3], multiple cores (Multi-minicore disease, MmD) with external ophthalmoplegia [4] and, rarely, Centronuclear Myopathy (CNM) [5]. Whilst MHS is dominantly inherited, CCD involves both dominant and recessive inheritance. MmD with external ophthalmoplegia is associated with recessive inheritance and quantitative defects of RyR1 protein expression, due to epigenetic allele silencing [6] or compound heterozygosity for RYR1 null and missense mutations [7], [8].

The periodic paralyses are a genetically heterogeneous group of rare, dominantly inherited conditions characterized by episodic weakness and divided into hyperkalaemic periodic paralysis (HYPP, OMIM 170500), mainly caused by SCN4A missense mutations [9], [10], and hypokalaemic periodic paralysis (HOKPP, OMIM170400), predominantly associated with mutations in the CACNA1S gene [11], which encodes the α1S subunit of the dihydropyridine receptor (DHPR) or L-type calcium channel in skeletal muscle. The close functional relationship between the DHPR and RyR1 is reflected by their co-localization and linkage within the triad [12], convergence of associated clinical phenotypes, and findings of abolished EC coupling in animal models lacking either of the two proteins [13], [14]. Whilst MHS has been reported in one French family harbouring a dominant CACNA1S mutation [15], prior studies failed to provide a definitive link between RYR1 mutations and periodic paralysis [16].

We report a 35-year-old patient with Multi-minicore disease (MmD) with external ophthalmoplegia and additional episodes of atypical periodic paralysis associated with compound heterozygosity for a nonsense and missense mutations in RYR. Detailed neurophysiological and immunohistochemical studies in this patient suggested a dramatic reduction in RyR1 protein expression with resulting marked disruption of the EC coupling machinery.

Section snippets

Patient

This 35-year-old female was the oldest child of a healthy non-consanguineous couple of Irish ancestry. Two younger brothers were healthy and her deceased sister had suffered from psychiatric problems. There was no preceding family history of neuromuscular disorders. She presented at birth with hypotonia, respiratory impairment and feeding difficulties following an uneventful pregnancy and normal vaginal delivery at term. Her motor development was delayed and she was unable to walk before 30 

Molecular genetic analysis of the RYR1 gene

An apparently homozygous nucleotide variation of c.8816G>A was identified in exon 57 of the RYR1 cDNA synthesized from patient’s skeletal muscle biopsy [22]. This maternally inherited missense mutation affects the last nucleotide of exon 57 and caused a substitution of p.Arg2939Lys. The p.Arg2939Lys mutation was not found neither in >200 normal control chromosomes from Caucasian populations nor among more than 50 previously reported MHS/CCD individuals of both Caucasian and Asian origin in whom

Discussion

The distribution of wasting and weakness, histopathologic features and radiological findings on muscle MRI in the patient reported in this paper are identical to those of other patients with Multi-minicore disease (MmD) with external ophthalmoplegia attributed to homozygosity [7], compound heterozygosity [4], [8] or monoallelic expression of heterozygous RYR1 missense mutations due to haploinsufficiency associated with either epigenetic allele silencing [6] or nonsense-mediated RNA decay [8].

Acknowledgements

We would like to thank the financial support from the Muscular Dystrophy Association USA, the National Institute of Health (AR044657 to R.T.D. and AR018687 to G.M.), and the NSCAG support to the Dubowitz Neuromuscular Centre. HJ has been supported by a grant from the Guy’s and St. Thomas’ Charitable Foundation and REL by a National Institutes of Health Dental and Craniofacial Training Grant (T32DE07202).

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