G.P.3 08 Novel mutations in the CHRNB1 gene in three patients affected by a congenital myasthenic syndrome

Abstract

Mutations of the nicotinic acetylcholine receptor (AChR) cause congenital myasthenic syndromes (CMS) by leading either to endplate AChR deficiency or to altered kinetic properties. Mutations in the alpha, beta and delta subunits of the AChR are less frequent than mutations of the epsilon subunit and often associated with a severe phenotype. So far, only five mutations of the gene encoding the beta subunit (CHRNB1) have been published. Here we present three CMS patients out of two families with mutations in the CHRNB1 gene. Two patients of Serbian origin, mother and daughter, presented with mild myasthenic syndromes in their late twenties. In each case, symptoms appeared during a pregnancy. At a neurological examination, mild ptosis and weakness of facial and upper extremities muscles were noted. A clear decremental response to repetitive nerve stimulation was obtained; repeated prostigmine tests did not show any clear improvement of the symptoms. The third patient, a girl currently 3 years of age, presented with an early-onset CMS associated with muscle hypotonia at birth, respiratory and feeding difficulties in the first weeks of life. Later on, apneic episodes occurred several times, especially during infections. At the age of 2 years, a CMS was diagnosed and acetylcholinesterase inhibitor therapy was started, which was only partially effective. By direct sequencing of the CHRNB1 gene we identified a heterozygous missense mutation (T265S) in the two Serbian patients. This mutation alters a conserved residue of the pore-forming second transmembrane region of the AChR beta subunit. In the third patient we identified two compound heterozygous mutations of the CHRNB1 gene: a nonsense mutation, Y149X, and a missense mutation, R220C. The arginine at position 220 in the extracellular domain of the beta subunit is highly conserved among species and AChR subunits. CHRNB1 mutations shall be considered as a rare cause of CMS. The pathogenic mechanisms of the mutations presented here remain to be investigated.