New mutation in the beta 1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome - Archive ouverte HAL Access content directly
Poster Communications Year : 2022

New mutation in the beta 1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome

Damien Sternberg
Thierry Maisonobe
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Abstract

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of inherited disorders caused by defective synaptic transmission at the neuromuscular junction, characterized by muscle weakness and fatigability. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and in rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A>G; p.Thy607Cys) within the 1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential (CMAP) in spinal nerves, associated with congenital agenesis of the hands and feet and renal malformation. Expression studies revealed the decrease of agrin and Wnt11 binding to mutated β1 propeller domain leading to a disruption of LRP4/MuSK signaling associated with a lack of AChR aggregation in patient myotubes. Little improvement in the patient's symptoms were observed with the treatments usually used for CMS. To date, mutations in the LRP4 gene have been reported in several different phenotypes including CLS and CMS but never associated together in the same patient. Besides, this study appears useful for the future diagnosis and treatment of patients with co-existing CLS and CMS and highlights the importance of structural and functional studies in the diagnosis and possible treatment of these atypical forms.

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Dates and versions

hal-03994163 , version 1 (17-02-2023)

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  • HAL Id : hal-03994163 , version 1

Cite

Stéphanie Bauché, Marion Masingue, Olivia Cattaneo, Damien Sternberg, Céline Buon, et al.. New mutation in the beta 1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome. journées de la société française de myologie, Nov 2022, Toulouse, France. ⟨hal-03994163⟩
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