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Human Endplate Acetylcholinesterase Deficiency Caused by Mutations in the Collagen-Like Tail Subunit (Colq) of the Asymmetric Enzyme

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Human Endplate Acetylcholinesterase Deficiency Caused by Mutations in the Collagen-Like Tail Subunit (Colq) of the Asymmetric Enzyme Proc. Natl. Acad. Sci. USA Vol. 95, pp. 9654–9659, August 1998 Physiology Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme KINJI OHNO,JOAN BRENGMAN,AKIRA TSUJINO, AND ANDREW G. ENGEL* Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Mayo Foundation, Rochester, MN 55905 Communicated by Clara Franzini-Armstrong, The University of Pennsylvania School of Medicine, Philadelphia, PA, May 19, 1998 (received for review April 3, 1998) ABSTRACT In skeletal muscle, acetylcholinesterase The proline-rich attachment domain (PRAD) of each strand (AChE) exists in homomeric globular forms of type T catalytic can bind an ACHET tetramer producing the asymmetric A4, subunits (ACHET) and heteromeric asymmetric forms com- A8, and A12 moieties (8). Asymmetric AChE is concentrated posed of 1, 2, or 3 tetrameric ACHET attached to a collagenic at the EP where it is the predominant species of AChE (9, 10). tail (ColQ). Asymmetric AChE is concentrated at the endplate In humans, all molecular forms of the catalytic subunit are (EP), where its collagenic tail anchors it into the basal lamina. encoded by one AChE gene (6, 11, 12). In muscle fibers, exons The ACHET gene has been cloned in humans; COLQ cDNA has 2–4 (which encode the catalytic domain) spliced to exon 6 been cloned in Torpedo and rodents but not in humans. In a encode ACHET. COLQ cDNA has been cloned and sequenced disabling congenital myasthenic syndrome, EP AChE defi- from Torpedo electric organ (13) and rat muscle (14), and the ciency (EAD), the normal asymmetric species of AChE are partial genomic sequence of mouse COLQ has been deter- absent from muscle. EAD could stem from a defect that mined (14). The sequence of the human COLQ gene has not prevents binding of ColQ to ACHET or the insertion of ColQ been reported to date. into the basal lamina. In six EAD patients, we found no In 1977, Engel et al. (15) reported a patient with a severely mutations in ACHET. We therefore cloned human COLQ disabling congenital myasthenic syndrome associated with EP cDNA, determined the genomic structure and chromosomal AChE deficiency (EAD). Other patients with similar disorders localization of COLQ, and then searched for mutations in this were observed subsequently (16, 17). In these patients, AChE gene. We identified six recessive truncation mutations of is absent from the EP by enzyme cytochemical and immuno- COLQ in six patients. Coexpression of each COLQ mutant cytochemical criteria, and electron cytochemical studies reveal with wild-type ACHET in SV40-transformed monkey kidney no reaction product for the enzyme in the synaptic basal fibroblast (COS) cells reveals that a mutation proximal to the lamina. Owing to absence of the enzyme from the EP, synaptic ColQ attachment domain for ACHET prevents association of currents are prolonged and evoke repetitive muscle fiber ColQ with ACHET; mutations distal to the attachment domain action potentials. The presynaptic terminals are abnormally generate a mutant '10.5S species of AChE composed of one small and often are encased by Schwann cells, reducing the ACHET tetramer and a truncated ColQ strand. The '10.5S number of quanta released by nerve impulse, perhaps to species lack part of the collagen domain and the entire protect the postsynaptic region from desensitization and cat- C-terminal domain of ColQ, or they lack only the C-terminal ionic overloading. Despite reduced quantal release, at some domain, which is required for formation of the triple collagen EPs, the junctional folds degenerate, causing loss of AChR, helix, and this likely prevents their insertion into the basal and the junctional sarcoplasm contains apoptotic nuclei and lamina. degenerating membranous organelles. Density gradients ul- tracentrifugation of muscle extracts of four patients with EAD Acetylcholinesterase (AChE; enzyme classification 3.1.1.7) is revealed no asymmetric AChE found in normal muscle, but a the enzyme responsible for rapid hydrolysis of acetylcholine fifth patient who also had no AChE deposits at the EP had released at cholinergic synapses. At the normal endplate (EP), detectable extracted asymmetric AChE. In these patients, the AChE limits the number of collisions between acetylcholine kinetic properties of residual AChE in muscle as well as the and the acetylcholine receptor (AChR) and, hence, the dura- activity and kinetic properties of erythrocyte AChE were ACHE tion of the synaptic response (1). Inhibition of the enzyme normal. Mutation analysis of T in two EAD patients not included in this report revealed no abnormality, and SV40- results in prolonged exposure of AChR to acetylcholine, transformed monkey kidney fibroblast (COS) cells cotrans- causing desensitization of AChR (2), a depolarization block at fected with ACHE cloned from these two patients together physiologic rates of stimulation (3), and an EP myopathy T with Torpedo COLQ readily expressed asymmetric AChE (18). caused by cationic overloading of the postsynaptic region (4, Taken together, the above findings suggest that EAD in 5). humans who do not express asymmetric AChE stems from a Two classes of AChE are present in mammalian skeletal defect that prevents binding of ColQ to ACHE or the muscle (6, 7): (i) homomeric or globular forms that consist of T insertion of ColQ into the basal lamina. Here, we report monomers (G ), dimers (G ), or tetramers (G )oftheT 1 2 4 cloning of human COLQ cDNA, determination of the genomic isoform of the catalytic subunit (ACHE ), and (ii) heteromeric T structure and chromosomal localization of the gene, and forms that consist of ACHET subunits linked to a triple helical collagen-like tail subunit (asymmetric forms) or to hydropho- bic subunits. The function of the collagen-like tail is to anchor Abbreviations: AChE, acetylcholinesterase; ACHET, T isoform of catalytic subunit; AChR, acetylcholine receptor; COS, SV-40- catalytic subunits to the basal lamina. The tail is formed by the transformed monkey kidney fibroblast; EP, endplate; EAD, EP AChE triple helical association of three collagen-like strands, ColQ. deficiency; FISH, fluorescence in situ hybridization; PRAD, proline- rich attachment domain; RACE, rapid amplification of cDNA ends; The publication costs of this article were defrayed in part by page charge RT-PCR, reverse transcription–PCR. Data deposition: The sequence reported in this paper has been payment. This article must therefore be hereby marked ‘‘advertisement’’ in deposited in the GenBank database (accession no. AF057036). accordance with 18 U.S.C. §1734 solely to indicate this fact. A commentary on this article begins on p. 9070. © 1998 by The National Academy of Sciences 0027-8424y98y959654-6$2.00y0 *To whom reprint requests should be addressed. e-mail: age@ PNAS is available online at www.pnas.org. mayo.edu. 9654 Downloaded by guest on September 30, 2021 Physiology: Ohno et al. Proc. Natl. Acad. Sci. USA 95 (1998) 9655 identification of six truncation mutations of COLQ in six COLQ, we searched for mutations in both genes. We first patients with EAD. Coexpression of each COLQ mutant with analyzed ACHET by amplifying and directly sequencing coding wild-type ACHET in COS cells indicates that the mutant exons 2–4 and 6 and their flanking intronic regions (22). To peptide either fails to assemble with AChET or binds one search for mutations in COLQ, we used the partial genomic tetramer of AChET but is unlikely to insert into the basal sequence obtained as described above and amplified and lamina. directly sequenced 17 genomic DNA fragments covering 19 constitutive and 2 alternatively transcribed exons and their MATERIALS AND METHODS flanking intronic or untranslated regions. In patients 1, 3, 4, and 5, we also directly sequenced overlapping RT-PCR prod- Patients. Six patients with EAD, presently 12, 37, 7, 14, 8, ucts spanning the entire COLQ coding region. After identi- and 2 years of age, were studied. Four were male, and two were fying mutations in COLQ, we screened the patients’ relatives female. Clinical and EP findings in patients 2 (15) and 3 (case for the observed mutations by restriction analysis or allele- 4 in Refs. 16 and 17) were reported. All had severe myasthenic specific PCR. symptoms since birth, negative tests for anti-AChR antibodies, Construction of Expression Vectors. We amplified the 2 a decremental electromyographic response, and failed to re- entire coding regions of ACHET (nucleotides 189 to 1,853) spond to anticholinesterase medications. Except in patient 2, and COLQ (nucleotides 292 to 1,471) from normal muscle supramaximal nerve stimuli evoked a repetitive compound mRNA, cloned each product into the pTargeT Expression muscle fiber action potential. Patient 6 had two siblings who Vector (Promega), and confirmed the absence of PCR arti- died in early childhood of myasthenic symptoms; the other facts by sequencing the entire inserts. We introduced the patients have no similarly affected relatives. Studies of inter- S169X, E214X, R282X, 788insC, and 1082delC mutations into costal muscle specimens in each patient showed absence of EP COLQ cDNA in the pTargeT vector by using the QuickChange AChE, prolonged EP currents unaffected by cholinesterase Site-Directed Mutagenesis kit (Stratagene) as described (23). inhibitors, reduced quantal release by nerve impulse, and small To eliminate exons 2 and 3 (107del215) from COLQ, we used presynaptic endings often covered by Schwann cells. AChR the Seamless Cloning kit (Stratagene). The presence of desired channel kinetics, investigated in patients 4, 5, and 6, were mutations and the absence of unwanted mutations was con- normal. firmed by sequencing the entire insert, the promoter, and the Tissue Specimens. Intercostal muscle specimens were ob- polyA signal region. tained from patients, and control subjects without muscle Expression in COS Cells. COS-7 cells were grown and were disease undergoing thoracic surgery. All human studies were transfected 1 day after spreading by the DEAE-dextran m m in accord with the guidelines of the Institutional Review Board method (24) with 5 gofACHET cDNA and 5 g of wild-type m of the Mayo Clinic.
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