The spectrum of mutations causing end-plate acetylcholinesterase deficiency

Abstract

The end‐plate species of acetylcholinesterase (AChE) is an asymmetric enzyme consisting of a collagenic tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of the T isoform of the catalytic subunit (AChET) via a proline‐rich attachment domain. The principal function of the tail subunit is to anchor asymmetric AChE in the synaptic basal lamina. Human end‐plate AChE deficiency was recently shown to be caused by mutations in COLQ. We here report nine novel COLQ mutations in 7 patients with end‐plate AChE deficiency. We examine the effects of the mutations on the assembly of asymmetric AChE by coexpressing each genetically engineered COLQ mutant with ACHET in COS cells. We classify the newly recognized and previously reported COLQ mutations into four classes according to their position in ColQ and their effect on AChE expression. We find that missense mutations in the proline‐rich attachment domain abrogate attachment of catalytic subunits, that truncation mutations in the ColQ collagen domain prevent the assembly of asymmetric AChE, that hydrophobic missense residues in the C‐terminal domain prevent triple helical assembly of the ColQ collagen domain, and that other mutations in the C‐terminal region produce asymmetric species of AChE that are likely insertion incompetent. Ann Neurol 2000;47:162–170.

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

“…Muscle weakness has also been reported in humans deficient in endplate AChE [36]. It has been well documented that a deficiency of AChE results in a change in hind limb muscle function and decreased ability of the hind limb to resist fatigue [37].…”

Two Different Heparin-binding Domains in the Triple-helical Domain of ColQ, the Collagen Tail Subunit of Synaptic Acetylcholinesterase

“…In congenital myasthenic syndrome type 1c patients, several mutations in the ColQ gene impair folding of ColQ, avoiding enzyme secretion. In some cases, there are point mutations in the C-terminal domain of ColQ in which asymmetric AChE forms are produced but are not accumulated at the neuromuscular junction (2). Because the interaction of AChE with HSPGs has been proposed to represent a crucial step for AChE retention and localization, it has opened the question of whether these mutations in the C-terminal domain of ColQ modify its interaction with HSPGs.…”

“…In the case of asymmetric AChE, the collagen ColQ is responsible for the localization of the enzyme at the vertebrate neuromuscular junction. Inactivation of the ColQ gene in mice or mutations in the human ColQ gene result in the absence of enzyme accumulation at the neuromuscular junction and are the cause of a congenital myasthenic syndrome (type 1c) (1,2).…”

“…The collagen domain is characterized by Gly-Xaa-Yaa repeats and a high proportion of the stabilizing proline and hydroxyproline residues. The C-terminal domain is divided into a proline-rich region, important for triple-helix formation (5), and a cysteinerich region probably involved in the anchorage of AChE at the neuromuscular junction, since mutations in this region prevent the accumulation of AChE in congenital myasthenic syndrome type 1c patients (2).…”

Assembly and regulation of acetylcholinesterase at the vertebrate neuromuscular junction

“…Perlecan is a multifunctional heparin sulfate proteoglycan that is also concentrated on the synaptic basal lamina, and the carboxyl terminal domain of ColQ is necessary and sufficient for its attachment. Several mutations in the C-terminal domain of COLQ indicate that this region of the collagenic tail is essential for AChE localization at the synapse [14][15][16]. To determine whether the entire collagenic tail was necessary for attachment, or only the Cterminal domain, we generated several fusion proteins consisting of GFP fused to varying lengths of COLQ.…”