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

Institute for Biomedical Research, University of Birmingham, Birmingham, England, United Kingdom
The American Journal of Human Genetics (Impact Factor: 10.99). 09/2006; 79(2):390-5. DOI: 10.1086/506256
Source: PubMed

ABSTRACT Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.

Download full-text


Available from: Lihadh Al-Gazali, Jul 03, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to report the clinical phenotype and genetic analysis of two Indian families with Escobar syndrome (ES). The diagnosis of ES in both families was made on the basis of published clinical features. Blood samples were collected from members of both families and used in genomic DNA isolation. The entire coding regions and intron-exon junctions of the ES gene CHRNG (cholinergic receptor, nicotinic, gamma), and two other related genes, CHRND and CHRNA1, were amplified and sequenced to search for mutations in both families. Both families show a typical form of ES. Sequencing of the entire coding regions including the intron-exon junctions of the three genes did not yield any mutations in these families. In conclusion, it is possible that the mutations in these genes are located in the promoter or deep intronic regions that we failed to identify or the ES in these families is caused by mutations in a different gene. The lack of mutations in CHRNG has also been reported in several families, suggesting the possibility of at least one more gene for this syndrome.
    Clinical dysmorphology 04/2013; 22(2):54-8. DOI:10.1097/MCD.0b013e32835f9ac0 · 0.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fetal akinesia deformation sequence is a clinically and genetically heterogeneous disorder characterized by a variable combination of arthrogryposis, fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, pulmonary hypoplasia, cleft palate, cryptorchidism, cardiac defects and intestinal malrotation, and occasional pterygia of the limbs. Multiple pterygium syndrome is a clinically and genetically heterogeneous disorder characterized by pterygia of the neck, elbows and/or knees, arthrogryposis, and other phenotypic features such as short stature, genital abnormalities, craniofacial abnormalities, clubfoot, kyphoscoliosis, and cardiac abnormalities. Fetal akinesia deformation sequence may phenotypically overlap with the lethal type of multiple pterygium syndrome. This article provides a comprehensive review of prenatal diagnosis and genetic analysis of fetal akinesia deformation sequence and multiple pterygium syndrome associated with neuromuscular junction disorders. Prenatal diagnosis of fetal akinesia along with cystic hygroma, increased nuchal translucency, nuchal edema, hydrops fetalis, arthrogryposis, pterygia, and other structural abnormalities should include a differential diagnosis of neuromuscular junction disorders. Genetic analysis of mutations in the neuromuscular junction genes such as CHRNA1, CHRND, CHRNG, CNTN1, DOK7, RAPSN, and SYNE1 may unveil the pathogenetic cause of fetal akinesia deformation sequence and multiple pterygium syndrome, and the information acquired is helpful for genetic counseling and clinical management.
    Taiwanese journal of obstetrics & gynecology 03/2012; 51(1):12-7. DOI:10.1016/j.tjog.2012.01.004 · 1.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autozygosity mapping has been invaluable for determining the genetic basis of lethal autosomal recessive disorders, but this approach remains challenging because DNA from affected individuals may often be unavailable or of insufficient quality for extensive molecular genetic studies. To circumvent these difficulties, we developed a computer program called "SAMPLE" (for shadow autozygosity mapping by linkage exclusion) to enhance autozygosity mapping through the empirical analysis of haplotypes of unaffected individuals in consanguineous families. Single nucleotide polymorphism (SNP) genotyping of unaffected individuals in complex consanguineous pedigrees is used to infer limited chromosomal regions compatible with linkage to a potential disease locus, and to allow the immediate prioritization of potential regions of interest. Further limited genotyping then enables the rapid confirmation and fine mapping of a disease locus. We demonstrate the utility of this strategy by using genotyping data from only parents and unaffected siblings, in three consanguineous families affected with Meckel-Gruber syndrome, to correctly infer the location of the MKS3/TMEM67 locus on chromosome 8q22.1. This strategy is practicable only with the recent advances in whole genome genotyping by high-density SNP microarrays, and could not be easily implemented in approaches that rely on microsatellite markers. SAMPLE is available at
    Human Mutation 12/2009; 30(12):1642-9. DOI:10.1002/humu.21105 · 5.05 Impact Factor