Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C‐terminal amino acid sequence. Issue 7 (6th April 2020)

• Record Type: Journal Article
• Authors: Maselli, Ricardo A.; van der Linden, Hélio; Ferns, Michael
• Is Part Of: American journal of medical genetics. Volume 182:Issue 7(2020)
• Page Start: 1744
• Page End: 1749
• Publication Date: 2020-04-06
• Subjects: congenital myasthenic syndrome -- recessive -- synaptic vesicles -- synaptotagmin 2; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.61579
• Languages: English
• ISSNs: 1552-4825

Abstract

Abstract: Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2 . The affected 2‐year‐old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert–Eaton myasthenic syndrome. 3, 4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x‐ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin‐SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2‐CMS and highlights the importance of the synaptotagmin C‐terminal on synaptic vesicle fusion and exocytosis.