Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine
Introduction
Congenital myasthenic syndromes (CMS) comprise a group of disorders in which the safety margin of neuromuscular transmission is compromised by mutations in genes encoding proteins of the presynaptic, synaptic, or postsynaptic regions [1]. CMS associated with deficiency of the acetylcholine receptor (AChR) at the endplate (EP) are due either to decreased synthesis or increased degradation of mutant receptors, or to failure of normal AChRs to localize and remain anchored at the postsynaptic membrane [1]. Rapsyn, a 43 kDa protein, functions to cluster AChRs at the postsynaptic membrane through interactions with the long cytoplasmic loop of subunits of the AChR [2] and with β-dystroglycan [3], [4], [5]. Mutations in the RAPSN gene encoding rapsyn have recently been recognized to cause CMS of variable clinical severity [6], [7], [8], [9], [10]. CMS due to mutations in the E-box consensus sequence of the RAPSN promoter lead to a relatively mild clinical phenotype, including a distinct facial malformation characterized by mandibular prognathism and jaw malocclusion in a group of Iranian and Iraqi Jews [7]. We here report two novel mutations in RAPSN and the associated clinical, morphologic, and electrophysiologic features.
Section snippets
Muscle specimens
Intercostal muscle specimens were obtained intact, from origin to insertion, from Pt 1 and from control subjects undergoing thoracic surgery. All human studies were in accord with the guidelines of the institutional review board of the Mayo Clinic.
Acetylcholinesterase (AChE) was visualized on glutaraldehyde-fixed teased single muscle fibers by Gautron's method [11]. AChR and AChE were colocalized in cryostat sections with rhodamine-labeled α-bungarotoxin (α-bgt) and a monoclonal anti-AChE
Patients
Patient (Pt) 1, a boy currently aged 14 years, had weak fetal movements in utero, and was delivered at term by caesarean section due to breech presentation. Hypotonia and limited limb movements were noted from birth. Ocular movements were normal and ptosis was absent at birth. Intermittent episodes of respiratory failure necessitated the use of mechanical ventilation for the first three months of life. At six months of age, during a severe episode of pneumonia, edrophonium was administered
Discussion
We describe two children with CMS with novel mutations in RAPSN. Each patient carries N88K; Pt 1 also carries 1177delAA, and Pt 2 also carries E333X. The N88K mutation has been previously characterized and shown to markedly impair co-clustering of rapsyn with the AChR [6]. The E333X mutation truncates rapsyn N-terminal to the RING-H2 domain and the 1177delAA mutation disrupts the RING-H2 domain; thus, both mutations likely interfere rapsyn binding to β-dystroglycan and, via dystroglycan, to the
Acknowledgements
This work was supported by NIH Grant NS6277 (to A.G.E.) and by a grant from the Muscular Dystrophy Association (to A.G.E.).
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