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Published online 6 March 2013
Congenital myasthenic syndromes (CMS) is a group of inherited disorders characterised by muscle weakness caused by impaired signalling between motor neurons and their muscle cell targets.
A new multinational study led by David Beeson of the University of Oxford and including Mustafa Salih of King Saud University, Riyadh, and Mohammed Zain Seidhamed of the Security Forces Hospital, Riyadh, has found that mutations in two new genes, ALG14 and ALG2, can cause CMS.
The researchers found that mutations in ALG14 and ALG2 affect either the transmission or reception of signalling by the neurotransmitter acetylcholine.
Both of these genes encode enzymes involved in asparagine (N)-linked glycosylation, a process important for protein stability, transport and localisation.
In the absence of proper N-linked glycosylation, the various subunits of the acetylcholine receptor fail to assemble efficiently, resulting in reduced levels of the receptor on the cell surface, causing the myasthenia.
Mutations in ALG2 and other genes in the N-linked glycosylation pathway have previously been found to underlie far more extensive multisystem disorders with widespread developmental and neurological effects. The recently discovered mutations are therefore likely responsible for partial impairment of N-linked glycosylation only.
"It is surprising that symptoms in these patients are largely restricted to defects of neuromuscular transmission, "says David Beeson. "But the results imply that treatment with drugs that enhance neuromuscular transmission, such as pyridostigmine, may benefit muscle function in these more severe disorders of N-linked glycosylation."