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Characterization of a new class of congenital myopathies

Muscle cells of patients with a congenital myopathy due to DHPR mutations, with small abnormal fibers with internalized nuclei (left), « core »-like intermyofibrillar disorganizations (center), and alveolar aspect of the sarcoplasmic reticulum (right).

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Schartner V(1,)(2,)(3,)(4), Romero NB(5,)(6), Donkervoort S(7), Treves S(8,)(9), Munot P(10), Pierson TM(11,)(12), Dabaj I(13,)(14,)(15), Malfatti E(5,)(6), Zaharieva IT(10), Zorzato F(8,)(9), Abath Neto O(1,)(7), Brochier G(5,)(6), Lornage X(1,)(2,)(3,)(4), Eymard B(16), Taratuto AL(17), Bohm J(1,)(2,)(3,)(4), Gonorazky H(18), Ramos-Platt L(19), Feng L(10), Phadke R(10), Bharucha-Goebel DX(7,)(20), Sumner CJ(21,)(22), Bui MT(5,)(6), Lacene E(5,)(6), Beuvin M(5,)(6), Labasse C(5,)(6), Dondaine N(23), Schneider R(1,)(2,)(3,)(4,)(24), Thompson J(24), Boland A(25), Deleuze JF(25), Matthews E(10), Pakleza AN(26), Sewry CA(10), Biancalana V(1,)(2,)(3,)(4,)(23), Quijano-Roy S(13,)(14,)(15,)(27), Muntoni F(10), Fardeau M(5,)(6), Bonnemann CG(7), Laporte J(28,)(29,)(30,)(31).

Acta Neuropathol Apr 2017

Dec. 23, 2016

The team of Jocelyn Laporte identified and characterized a new class of congenital myopathies, offering new diagnosis prospects for undiagnosed patients. This work was published on the 23rd December in the journal Acta Neuropathologica.


Congenital myopathies: undiagnosed patients
There are three major groups of congenital myopathies distinguished by the structural anomalies of the muscle fibers studied by microscopy: myopathies with focal disorganization of the fibers, called “cores”, myopathies with protein aggregates, and centronuclear myopathies. Despite the recent identification of implicated genes, half of the patients with congenital myopathy are still devoid of a molecular diagnosis and are thus non-classified, precluding better healthcare and genetic counseling. In the frame of the Myocapture project, the team of Jocelyn Laporte collaborated with the team of Norma Beatriz Romero from the Institute of Myology (Paris) and an international consortium in order to characterize 1000 undiagnosed patients. Among those patients, 11 were selected based on common features found on their muscle biopsies, including an “alveolar” aspect of the muscle cells due to the dilatation of the sarcoplasmic reticulum, the essential calcium store for the muscle contraction.


Mutations in a calcium channel essential for muscle contraction
By high-throughput sequencing of the DNA of these 11 patients, the researchers revealed that all of them had mutations in the same gene CACNA1S, coding for a subunit of the dihydropyridine receptor (DHPR), a calcium channel essential for muscle contraction. Surprisingly, these mutations are widespread in the gene and are either from recessive or dominant transmission. Functional experiments done in collaboration with the University of Basel showed that the mutated DHPR calcium channels are less efficient and that calcium signaling is altered.
The gene CACNA1S was already well studied because of its implication in other diseases such as malignant hyperthermia and hypokalemic or thyrotoxic periodic paralysis, but this is the first time that this gene is associated with a myopathy. This confirms the importance of the DHPR channel in muscle development and contraction.

This study reveals a new class of congenital myopathies and highlights the DHPR channel as a new therapeutic target to treat congenital myopathies.


This study is funded by investissements d’avenir Labex, the University of Strasbourg, Inserm, Fondation Maladie Rares, France Génomique, ANR, Association Française contre les Myopathies, Muscular Dystrophy Association and Myotubular Trust.

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