Abstract
The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
Highlights
Muscle contraction is a multistep process involving the conversion of an electrical stimulus into mechanical force, and disturbances of this cascade of events can severely impact on muscle physiology and lead to humanBiancalana et al acta neuropathol commun (2021) 9:155 disorders
The functionality of the excitation–contraction coupling (ECC) machinery essentially relies on the skeletal muscle triad, a specialized membrane complex composed of a deep sarcolemma invagination known as T-tubule and two flanking terminal cisternae of the sarcoplasmic reticulum (SR) [12]
Mutations in RYR1 have been associated with a variety of dominant and recessive pathologies including malignant hyperthermia susceptibility (MHS, OMIM #145,600) [16, 25], King-Denborough syndrome [6], central core disease (CCD, OMIM #117,000) [29, 38], multi-minicore disease (MmD, OMIM #255,320) [26], centronuclear myopathy [36], congenital fiber-type disproportion (CFTD) [5], core-rod myopathy [28], dusty core disease (DuCD) [15], late-onset axial myopathy [24], Samaritan myopathy [3], and exertional myalgia [9]
Summary
Muscle contraction is a multistep process involving the conversion of an electrical stimulus into mechanical force, and disturbances of this cascade of events can severely impact on muscle physiology and lead to humanBiancalana et al acta neuropathol commun (2021) 9:155 disorders. ECC is driven by the voltage-gated L-type C a2+ channel DHPR (dihydropyridine receptor) at the T-tubules and the Ca2+ channel RyR1 (ryanodine receptor 1) at the SR. DHPR undergoes a conformational change and activates RyR1 across the membrane gap to trigger Ca2+ release from the SR. The vast majority of the CCD mutations are heterozygous missense changes mainly affecting conserved amino acids in the C-terminal part of the protein, and functional studies have shown that the mutations either generate a leaky RyR1 channel, or interfere with DHPR binding, and thereby uncouple excitation from contraction [1, 8, 23]. Muscle biopsies from CCD patients display well-delimited areas with reduced oxidative activity and a variable degree of sarcomeric disorganization running along the longitudinal fiber axis as histopathological hallmark [18]
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