<i>CHRNG</i>genotype–phenotype correlations in the multiple pterygium syndromes

Vogt, Julie; Morgan, Neil V.; Rehal, Pauline K.; Faivre, Laurence; Brueton, Louise; Becker, Kristin; Fryns, Jean‐Pierre; Holder, Sue; Islam, Lily; Kivuva, Emma; Lynch, Sally Ann; Touraine, Renaud; Wilson, Louise C.; Macdonald, Fiona; Maher, Eamonn R.

doi:10.1136/jmedgenet-2011-100378

Cited by 43 publications

(58 citation statements)

References 15 publications

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“…MPS has both lethal (OMIM 253290) and nonlethal (Escobar variant) (OMIM 265000) types. 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.…”

Section: Resultsmentioning

confidence: 99%

“…Although GPR126 mutations were recently associated with arthrogryposis, MYBPC2 may also be considered as a contributory gene to the patient's phenotype due to the gene function and interactome structure of its protein product. affected sibling had nonlethal MPS (15,20). Moreover, the same family had 4 additional cousins with nonlethal MPS phenotype and 1 deceased cousin.…”

Section: Discussionmentioning

confidence: 98%

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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

103

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Bayram

Karaca

Akdemir

et al. 2016

Journal of Clinical Investigation

103

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“…2 However, the impact of the CHRNG mutational spectrum on its clinical manifestation remains unclear. 3,4 Using whole-exome sequencing (WES) technique, we demonstrate that two independent Korean kindred of congenital arthrogryposis multiplex without typical features of Escobar syndrome showing severe pterygium are caused by rare, but identical, mutations in CHRNG.…”

Section: Introductionmentioning

confidence: 99%

Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations

et al. 2015

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Multiple pterygium syndrome (MPS) is an autosomal recessively inherited condition that becomes evident before birth, with pterygium at multiple joints and akinesia. There are two forms of this syndrome that are differentiated by clinical severity: the milder form, Escobar type (OMIM#265000), and the more severe form, lethal type (OMIM#253290). Mutations in CHRNG, which encode the acetylcholine receptor gamma subunit, cause most cases of MPS. Here, we present three patients from two unrelated families showing multiple joint contractures in both the upper and lower limbs. High-arched palates with malocclusion, short neck and micrognathia were observed in all patients. Peripheral blood karyotypes were normal. Whole-exome sequencing analysis of the patients' genomes led to the discovery of identical missense (p.Pro143Arg) and frameshift deletion variants (p.Pro251fs*45) on CHRNG. These were rare cases of congenital arthrogryposis multiplex related to novel recessive CHRNG variants in two Korean kindred without apparent relatedness.

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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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CHRNGgenotype–phenotype correlations in the multiple pterygium syndromes

Cited by 43 publications

References 15 publications

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

Rare cases of congenital arthrogryposis multiplex caused by novel recurrent CHRNG mutations

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

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