Mutation in the Human Acetylcholinesterase-Associated Collagen Gene, COLQ, Is Responsible for Congenital Myasthenic Syndrome with End-Plate Acetylcholinesterase Deficiency (Type Ic)

Abstract

Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic). It is characterized by onset in childhood, generalized weakness increased by exertion, refractoriness to anticholinesterase drugs, and morphological abnormalities of the neuromuscular junctions (NMJs). The collagen-tailed form of AChE, which is normally concentrated at NMJs, is composed of catalytic tetramers associated with a specific collagen, COLQ. In CMS-Ic patients, these collagen-tailed forms are often absent. We studied a large family comprising 11 siblings, 6 of whom are affected by a mild form of CMS-Ic. The muscles of the patients contained collagen-tailed AChE. We first excluded the ACHE gene (7q22) as potential culprit, by linkage analysis; then we mapped COLQ to chromosome 3p24.2. By analyzing 3p24.2 markers located close to the gene, we found that the six affected patients were homozygous for an interval of 14 cM between D3S1597 and D3S2338. We determined the COLQ coding sequence and found that the patients present a homozygous missense mutation, Y431S, in the conserved C-terminal domain of COLQ. This mutation is thought to disturb the attachment of collagen-tailed AChE to the NMJ, thus constituting the first genetic defect causing CMS-Ic.

Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes

“…[7][8] One, two or three globular subunits form the main structure of this synaptic enzyme, which needs to be anchored to the basal lamina for its proper function. The…”

“…The kinetic mutations fall into two categories according to whether they induce slow or fast channel syndromes [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] .…”

“…These are the pre-synaptic acetyltransferase CHAT 6 , the gene COLQ 7-8-9 encoding the triple stranded collagenic tail of the synaptic acetylcholinesterase (AChE), the genes encoding the different subunits of the postsynaptic acetylcholine receptors (AChR) CHRNA1, CHRNB1, CHRND, CHRNE and CHRNG, the RAPSN gene encoding the postsynaptic protein rapsyn 10 , the postsynaptic muscle specific kinase (MUSK) gene 11 , the postsynaptic sodium channel (SCN4) 12 , the DOK7 gene encoding the postsynaptic Dok-7 protein [13][14] , the LAMB2 encoding the synaptic Laminin B2 protein 15 , the AGRN gene encoding the postsynaptic agrin protein 16 and the PLEC1 gene encoding the postsynaptic protein plectin. 17-18-19 Genetic classification of the different CMS cohorts reveals that the majority of CMS patients have mutations in genes expressing postsynaptic endplate proteins [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (table 1). Despite tremendous progress in identifying the molecular basis of the different CMS subtypes, almost half of the CMS population remains genetically undiagnosed.…”

Therapeutic Strategies in Congenital Myasthenic Syndromes

“…These are inherited disorders, caused by various genetic defects, and all but the slow-channel CMS by recessive inheritance. [1][2][3][4][5] To date, mutations in 10 different genes have been found to cause a CMS: CHAT, coding for the presynaptic choline acetyltransferase 6 ; COLQ, coding for the endplate acetylcholine esterase 7,8 ; CHRNA1, CHRNB1, CHRND, and CHRNE coding for four different AChR subunits 9,10 ; RAPSN, coding for the postsynaptic protein rapsyn 11 ; MUSK, coding for the muscle-specific kinase 12 ; DOK7, coding for the downstream of kinase 7 protein 13 ; and SCN4A, coding for the postsynaptic voltage-gated sodium channel Na v 1.4. 14…”

Transcriptional Regulation of Acetylcholinesterase-associated Collagen ColQ

“…Collagen ColQ thus characterizes the collagen-tailed forms (A forms) of AChE and butyrylcholinesterase (3)(4)(5), which are localized in the basal lamina at neuromuscular junctions (nmjs) of vertebrates (6,7); in these molecules (A 4 , A 8 , A 12 ), one, two, or three tetramers of catalytic subunits are disulfide-linked to the strands of a triple helix of ColQ collagen. The cDNAs encoding ColQ have been cloned in Torpedo and mammals (4,8,9). The primary structure of ColQ comprises a signal peptide, an N-terminal domain containing a proline-rich motif (PRAD) that associates with four C-terminal T peptides of AChE T or butyrylcholinesterase subunits, a collagenous domain with characteristic repeats of glycines every three residues, and a C-terminal region (10,11).…”