Profs. Susan Treves and Francesco Zorzato, University Hospital Basel

Abstract (lay summary see below)
 

Mutations in RYR1, the gene encoding the ryanodine receptor 1, the calcium channel of the sarcoplasmic reticulum, are the underlying cause of approximately 30% of all congenital myopathies. Patients usually present a range of phenotypes at a young age; these include developmental delays, muscle weakness, hypotonia and muscle stiffness that are primarily caused by defects in channel conductance or decreased amounts of ryanodine receptor protein, leading to less calcium being released from the sarcoplasmic reticulum. However, in addition to the skeletal muscle phenotype, many patients also present musculoskeletal defects including scoliosis, congenital hip dislocation, foot deformities, joint laxity etc. whose underlying causes have not been investigated.
Muscle spindles are an organ that is not involved in force generation, but act as mechanical sensors conveying information relating to muscle stretch and velocity of contraction to the central nervous system. This information is important not only for adjusting the tonic response of agonistic and antagonistic muscle groups, but also in modulating skeletal development. Indeed, patients with mutations in genes expressed in muscle spindles such as PIEZO2, exhibit musculoskeletal defects that are also present in patients harboring RYR1 mutations. We hypothesize that the skeletal deformities in patients harbouring RYR1 mutations are caused by malfunction of the intrafusal muscle fibres which make up the muscle spindles. Intrafusal muscle fibers which include nuclear bag fibers and nuclear chain fibers contain subplasmalemmal triads, a syncytium of sarcoplasmic reticulum and transverse tubules, i.e. the site of calcium release. In affected patients, mutations in RYR1 would cause abnormal calcium release from the ryanodine receptors 1 present in the intrafusal muscle fibers, bringing about an inappropriate response of the central nervous system ultimately leading to skeletal deformities during fetal development and/or growth.
We hypothesize that defective muscle spindle function is an etiological factor of the musculoskeletal defects in patients with RYR1-related congenital myopathy. We will investigate this by studying the role of ryanodine receptor 1 in intrafusal muscle fibers in: (i) a mouse model we created knocked in for compound heterozygous RyR1 mutations and (ii) in a muscle-spindle specific Ryr1 knock out mice.

Lay summary

Mutazioni nel RYR1, il gene codificante il recettore della rianodina (RyR1), sono la causa piu’
comune di malattie muscolari congenite nell’uomo, come la entral Core Disease, la Multi-minicore
Disease e la malattia Centronucleare. Molti pazienti affetti da queste patologie oltre a mostrare una
profonda debolezza muscolare, mostrano anche deformazioni del sistema scheletrico incluso scoliosi,
piede equino, pes cavus, cifosi, lassità articolare e contratture tendinee. Sino ad oggi nessuno studio si
è focalizzato sul nesso tra mutazioni nel RYR1 e deformazioni scheletriche.
L’obiettivo di questo progetto e’ di verificare se il malfunzionamento dei fusi muscolari,
causato da mutazioni nel RYRI sono la causa delle deformazioni scheletriche osservate nei pazienti con
mutazioni nel RYR1. I fusi muscolari sono un gruppo speciale di muscoli che giocano un ruolo
fondamentale nel trasmettere informazioni circa la velocità e l’estensione della contrazione muscolare,
al sistema nervoso centrale. Questo studio é importante perché permetterà di capire le basi molecolari
dei difetti scheletrici in questi pazienti, un passo fondamentale nel promuovere terapie per trattare i
pazienti affetti da malattie muscolari congenite dovute a mutazione nel RYR1.