Mutations in the Embryonal Subunit of the Acetylcholine Receptor (CHRNG) Cause Lethal and Escobar Variants of Multiple Pterygium Syndrome

Morgan, Neil V.; Brueton, Louise; Cox, Phillip; Greally, Marie T.; Tolmie, John; Pasha, Shanaz; Aligianis, Irene; Bokhoven, Hans van; Marton, T.; Al‐Gazali, Lihadh; Morton, Jenny; Oley, Christine; Johnson, Colin A.; Trembath, Richard C.; Brunner, Han G.; Maher, Eamonn R.

doi:10.1086/506256

Cited by 147 publications

(123 citation statements)

References 24 publications

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“…The common findings in these patients were prenatally detected restriction of movements; craniofacial dysmorphisms, including down-slanting palpebral fissures, low-set ears, and micrognathia; and multiple contractures of the limbs ( Figure 2B). The distribution of CHRNG mutations detected in our study is shown in Figure 2, C and D. Two of the identified CHRNG mutations have not been reported, while the other mutations, including the recurrent mutation, have been reported previously in MPS patients (20,36). In 1 of 3 patients with the same homozygous CHRNG mutation (BAB5611), we additionally identified another homozygous deleterious mutation in a different arthrogryposis gene, ERCC2 (c.1775G>A; p.Arg592His) (Figure 2A Other identified variants in known genes are delineated in Tables 1 and 2.…”

Section: Discussionsupporting

confidence: 46%

“…Although most of the MPS cases were reported with a pattern of autosomal-recessive inheritance (15), autosomal-dominant transmission was also observed in a few cases (16)(17)(18). While homozygous and compound heterozygous mutations of CHRNG (19,20) were associated with both lethal and nonlethal types of MPS, mutations of CHRND (21) and CHRNA1 (21) are also responsible for lethal MPS. Recently, homozygous mutations in RYR1 (22) and autosomal-dominant inheritance with MYH3 mutations were reported in MPS patients (23).…”

Section: Resultsmentioning

confidence: 99%

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Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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Section: Discussionsupporting

confidence: 46%

Section: Resultsmentioning

confidence: 99%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

111

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“…Expressing human AChR γ-subunit in ε -/-mice rescues the lethality of the ε-subunit gene deletion, but the rescued mice continue to display AChR deficiency and develop phenotypes similar to human congenital myasthenic syndromes (Cossins et al, 2004). Furthermore, mutations in human AChR γ-subunit gene (CHRNGHuman Gene Nomenclature Database) cause severe prenatal myasthenia (Escobar or multiple pterygium syndrome) (Hoffmann et al, 2006;Morgan et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning

et al. 2008

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Formation of the vertebrate neuromuscular junction (NMJ) takes place in a stereotypic pattern in which nerves terminate at select sarcolemmal sites often localized to the central region of the muscle fibers. Several lines of evidence indicate that the muscle fibers may initiate postsynaptic differentiation independent of the ingrowing nerves. For example, nascent acetylcholine receptors (AChRs) are pre-patterned at select regions of the muscle during the initial stage of neuromuscular synaptogenesis. It is not clear how these pre-patterned AChR clusters are assembled, and to what extent they contribute to pre-and post-synaptic differentiation during development. Here, we show that genetic deletion of the AChR γ-subunit gene in mice leads to an absence of pre-patterned AChR clusters during initial stages of neuromuscular synaptogenesis. The absence of pre-patterned AChR clusters was associated with excessive nerve branching, increased motoneuron survival, as well as aberrant distribution of acetylcholinesterase (AChE) and rapsyn. However, clustering of muscle specific kinase (MuSK) proceeded normally in the γ-null muscles. AChR clusters emerged at later stages owing to the expression of the AChR epsilon-subunit, but these delayed AChR clusters were broadly distributed and appeared at lower level compared with the wild-type muscles. Interestingly, despite the abnormal pattern, synaptic vesicle proteins were progressively accumulated at individual nerve terminals, and neuromuscular synapses were ultimately established in γ-null muscles. These results demonstrate that the γ-subunit is required for the formation of pre-patterned AChR clusters, which in turn play an essential role in determining the subsequent pattern of neuromuscular synaptogenesis.

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“…In mice, the γ-subunit KO is lethal (6), and in humans, mutations in the cholinergic receptor, nicotinic, gamma (CHRNG) gene that encodes for γ-subunit are associated with lethal forms of multiple pterygium and Escobar syndromes (7)(8)(9).…”

mentioning

confidence: 99%

Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response

Nayak

Auerbach

2013

Proc. Natl. Acad. Sci. U.S.A.

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Neuromuscular acetylcholine receptors (AChRs) have two transmitter binding sites: at α−δ and either α−γ (fetal) or α-e (adult) subunit interfaces. The γ-subunit of fetal AChRs is indispensable for the proper development of neuromuscular synapses. We estimated parameters for acetylcholine (ACh) binding and gating from single channel currents of fetal mouse AChRs expressed in tissuecultured cells. The unliganded gating equilibrium constant is smaller and less voltage-dependent than in adult AChRs. However, the α−γ binding site has a higher affinity for ACh and provides more binding energy for gating compared with α−e; therefore, the diliganded gating equilibrium constant at −100 mV is comparable for both receptor subtypes. The −2.2 kcal/mol extra binding energy from α−γ compared with α−δ and α−e is accompanied by a higher resting affinity for ACh, mainly because of slower transmitter dissociation. End plate current simulations suggest that the higher affinity and increased energy from α−γ are essential for generating synaptic responses at low pulse [ACh].are ligand-gated ion channels comprised of five subunits: two α(1) and one each of β, δ, and either γ or e. In most species, the γ-subunit is replaced by e during postnatal development. Electrical activity in muscle cells induced by the neurotransmitter acetylcholine (ACh) is important for the molecular maturation of γ-to e-AChRs (1, 2).Without γ-subunit, neuromuscular synapses do not develop properly (3) and are abnormal in innervation patterns (4) and muscle fiber-type composition (5). In mice, the γ-subunit KO is lethal (6), and in humans, mutations in the cholinergic receptor, nicotinic, gamma (CHRNG) gene that encodes for γ-subunit are associated with lethal forms of multiple pterygium and Escobar syndromes (7-9).AChRs have two transmitter binding sites located in the extracellular domain at α-δ and α-γ/e-subunit interfaces. In adult AChRs, the α−δ and α−e sites are equal and independent insofar as each has the same affinity for ACh and supplies the same amount of binding energy for gating (10). In fetal AChRs, the two binding sites are asymmetric with regard to agonist affinity, with estimates for the ratio of resting equilibrium dissociation constants for ACh ranging from ∼5-(11, 12) to >100-fold (13, 14). γ-AChRs also have a longer open channel lifetime, a smaller unitary conductance, and a lower Ca 2+ permeability than e-AChRs (15-17).Fetal AChRs hold a special place in the history of ion channel biophysics. The first single channel recordings from cells were of γ-AChRs (18). They were also the first ion channels to be analyzed according to a thermodynamic cycle, which required quantifying constitutive activity in the absence of agonists (19). These pioneering studies of single channel currents from mouse myotubes led to the estimate that the unliganded gating equilibrium constant of γ-AChRs is ∼1.6 × 10 −6 . γ-AChRs were also the first channels for which the rate and equilibrium constants for closed channel binding and liganded gating were measured (13,(...

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Mutations in the Embryonal Subunit of the Acetylcholine Receptor (CHRNG) Cause Lethal and Escobar Variants of Multiple Pterygium Syndrome

Cited by 147 publications

References 24 publications

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning

Asymmetric transmitter binding sites of fetal muscle acetylcholine receptors shape their synaptic response

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