Congenital myasthenic syndromes (CMS) are characterised by a dysfunction of the transmission of the nerve influx at the level of the neuromuscular junction, causing muscle weakness and fatiguability. Different genes have been identified for this group of diseases, such as the choline acetyltransferase gene, the COLQ gene encoding an achetylcholineesterase subunit and the genes of different subunits of the (RACh) acetylcholine receptor.

Kinji Ohno, a researcher at the Center for Neurological Diseases and Cancer (Nagoya University Graduate School of Medicine), presented his laboratory’s latest discoveries. His team has identified new mutations in the COLQ and CHRNE (a subunit of RACh) genes which cause splicing deterioration*. They estimate that more than 20% of missense mutations affect the splice sites, while the figure in other studies was far lower.
* Splicing is a molecular mechanism which converts pre-RNA from the nucleus into mature messenger RNA.
Contribution from Kinji Ohno – Splicing abnormalities in congenital myasthenic syndromes

 

This first contribution was followed by that of Daniel Hantaï, a researcher at Inserm Unit 582 (Institute of Myology, Paris). French researchers reported the case of a 27-year old woman CMS patient carrying two different mutations in the MUSK (muscle-specific receptor tyrosine kinase) gene. From birth, the patient developed respiratory distress and ptosis. At 22 years old the symptoms worsened, with a generalised weakness of the upper and lower limb muscles. The MUSK protein plays a key role in the formation of the neuromuscular junction.
Contribution from Daniel Hantaï – Pathophysiological characterisation of congenital myasthenic syndromes: the example of mutations in the MUSK gene.

 

There are three early-onset myopathies linked to mutations of the selenoprotein N gene (SEPN1): Rigid Spine muscular Dystrophy (RSMD), multi-minicore congenital myopathy and the desmin-related myopathy with Mallory body-like inclusions. These three diseases represent a new nosological entity termed SEPN-related myopathies or seleopathies. Selenoprotein N contains one selenocysteine residue which is inserted in the UGA codon of exon 10. Surprisingly, this UGA codon is not read as a classic stop codon due to specific sequences such as SECIS (sec insertion sequence: selenocysteine insertion site) which gives the RNA a very particular structure (stem-loop structures) and prevents its reading by ribosome.
Pascale Guicheney (Inserm Unit 582, Institute of Myology) presented the results of collaborative French work on 80 selenopathy-affected patients. Of the 48 mutations identified, the researchers discovered several which affect the stem-loop structures of the RNA. The results suggest that these mutations prevent the formation of these structures in loop and consequently selenocysteine incorporation and selenoprotein synthesis. This hypothesis put forward by French researchers represents a new physiopathological mechanism of selenopathies.
Contribution from Pascale Guicheney – New mutations altering the co-translational incorporation of the selenocysteine residue into selenoprotein N.

 

Recent discoveries have led to the identification of a group of congenital muscular dystrophies (CMD) characterised by a glycosylation deficiency of alpha-dystroglycane (alphaDG): Fukuyama congenital muscular dystrophy (fukutin gene), muscle-eye-brain syndrome (POMGnT1 gene), Walker-Warburg syndrome (POMT1 gene) and CMD1C (LARGE gene). However, only the POMGnT1 and POMT1 genes possess intrinsic glycosyltransferase activity (necessary for the glycosylation of alphaDG).
Tatsushi Toda (Department of Medical Genetics, University of Medicine, Osaka) presented his team’s latest work in this field. The Japanese researchers have shown that fukutin is able to interact with POMTGnT1, to form a complex with it and to modulate its enzymatic activity. In fact, in the absence of fukutin the glycosyltransferase activity of POMGnT1 decreased by about 30%. With these results, the involvement of fukutin in the glycosylation of alphaDG can be explained.
Contribution from Tatsushi Toda – Fukutin interacts with and modulates POMGnT1.

 

Although it has been little-studied, the interaction between muscles and joints is important to the motor function and is involved in certain diseases such as collagenopathies (collagen deficiency). J. Andoni Urtizberea (AFM, Institute of Myology, Paris) presented two very interesting new clinical cases characterised both by a lengthening/enlargement of the joints and muscle weakness. The first patient, from a cosanguineous Syrian family, presented with muscle weakness and chronic painful joints. A diagnosis of progressive pseudoepiphyseal dysplasia (PPD) was arrived at by molecular analyses. In the second patient, the clinicians observed a lengthening/enlargement of the joints, walking difficulties and arthrogryposis. Genetic examinations confirmed the diagnosis of infantile systemic hyalinosis. These two diseases could be included in the differential diagnosis at clinical examination in cases of muscle weakness and damage to joints.
Contribution from J. Andoni Urtizberea – Enlarged joints and muscle weakness: two paradigmatic case reports.

 

Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM) is characterised by the presence of rimmed vacuoles and variation of muscle fibre size. This disease is due to mutations in the GNE gene, an enzyme necessary in the synthesis of sialic acid. In a study presented by Ichizo Nishino (Department of Neuromuscular Research, National Institute of Neurosciences, Tokyo), researchers identified GNE mutations in 60 HIBM patients. Interestingly, the cardiac muscle and brain white matter were also affected. No phenotype-genotype correlation was observed. In vitro experiments indicated that the GNE mutations induced a decrease in enzymatic activity and hyposialylation of myotubes, suggesting that this could play a physiopathological role in HIBM.
Contribution from Ichizo Nishino – Distal myopathy with rimmed vacuoles: molecular pathomechanism.

 

Schwartz-Jampel syndrome (SJS) is a hereditary disease characterised by myotonia and early-onset chondrodysplasia. This pathology is due to mutations in the perlecan gene, which codes for a protein of the basal lamina. In contrast to other myotonic syndromes, SJS is not therefore associated with a deterioration of a voltage-dependent ion channel. Sophie Nicole (Inserm Unit 546, Faculty of Medicine, Pitié-Salpêtrière Hospital, Paris) presented the work of her team, which aimed to explain the link between a defect of the basal lamina component and skeletal muscle hyperexcitability. For this, researchers established a phenotype-genotype correlation in 35 SJS patients (with 26 mutations identified). Moreover, a murine model of SJS carrying a homozygous mutation is at present under study.
Contribution from Sophie Nicole – Schwartz-Jampel syndrome and perlecan mutations: genotype-phenotype correlation and development of an animal model.