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: 10.93). 09/2006; 79(2):390-5. DOI: 10.1086/506256
Source: PubMed


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.

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Available from: Lihadh Al-Gazali
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    • "intronic regions that we failed to identify as we sequenced only the coding region and intron–exon junction or these families actually map to a different locus, suggesting genetic heterogeneity. Similarly, in eight of the nine families with no mutations in CHRNG, Morgan et al. (2006) excluded linkage to the CHRNG locus, suggesting the presence of at least one more locus for the ES. As mutations in the CHRND and CHRNA1 genes result in the lethal type of MPS, we also sequenced the entire coding regions and intron–exon junctions of these genes. "
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    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.
    Full-text · Article · Apr 2013 · Clinical dysmorphology
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    • "Chrng (Cholinergic receptor, nicotinic, gamma) is a transmembrane glycoprotein and has been shown to play a role in neuromuscular organogenesis and ligand binding [42]. Mutation of Chrng causes the developmental disorder multiple pterygium syndrome in humans, exhibited by isolated CP, short stature, vertebral (spine) defects, joint contractures, and webbing of the neck, armpit, elbow, and knee [42,43]. Pterygium is also associated with Irf6 and p63 mutations in humans [44], and both Irf6 and p63 are known to be closely associated with TGFβ signaling. "
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    ABSTRACT: Background In humans, cleft palate (CP) accounts for one of the largest number of birth defects with a complex genetic and environmental etiology. TGFβ3 has been established as an important regulator of palatal fusion in mice and it has been shown that TGFβ3-null mice exhibit CP without any other major deformities. However, the genes that regulate cellular decisions and molecular mechanisms maintained by the TGFβ3 pathway throughout palatogenesis are predominantly unexplored. Our objective in this study was to analyze global transcriptome changes within the palate during different gestational ages within TGFβ3 knockout mice to identify TGFβ3-associated genes previously unknown to be associated with the development of cleft palate. We used deep sequencing technology, RNA-Seq, to analyze the transcriptome of TGFβ3 knockout mice at crucial stages of palatogenesis, including palatal growth (E14.5), adhesion (E15.5), and fusion (E16.5). Results The overall transcriptome analysis of TGFβ3 wildtype mice (C57BL/6) reveals that almost 6000 genes were upregulated during the transition from E14.5 to E15.5 and more than 2000 were downregulated from E15.5 to E16.5. Using bioinformatics tools and databases, we identified the most comprehensive list of CP genes (n = 322) in which mutations cause CP either in humans or mice, and analyzed their expression patterns. The expression motifs of CP genes between TGFβ3+/− and TGFβ3−/− were not significantly different from each other, and the expression of the majority of CP genes remained unchanged from E14.5 to E16.5. Using these patterns, we identified 8 unique genes within TGFβ3−/− mice (Chrng, Foxc2, H19, Kcnj13, Lhx8, Meox2, Shh, and Six3), which may function as the primary contributors to the development of cleft palate in TGFβ3−/− mice. When the significantly altered CP genes were overlaid with TGFβ signaling, all of these genes followed the Smad-dependent pathway. Conclusions Our study represents the first analysis of the palatal transcriptome of the mouse, as well as TGFβ3 knockout mice, using deep sequencing methods. In this study, we characterized the critical regulation of palatal transcripts that may play key regulatory roles through crucial stages of palatal development. We identified potential causative CP genes in a TGFβ3 knockout model, which may lead to a better understanding of the genetic mechanisms of palatogenesis and provide novel potential targets for gene therapy approaches to treat cleft palate.
    Full-text · Article · Feb 2013 · BMC Genomics
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    • "The fetus manifested hydrops at 13 weeks of gestation and was terminated at 15 weeks of gestation with down-slanting palpebral fissures, low-set ears, micrognathia, deviation of the wrists, bilateral talipes, unfixed colon, mild thoracic scoliosis, and reduced muscle bulk. Morgan et al [18] additionally reported a 37-gestational-week female fetus in a non-consanguineous family with hydrops, bilateral pleural effusions, skin edema, hydronephrotic right kidney, pterygia, rocker-bottom feet, lung hypoplasia, neonatal death, and a homozygous frameshift mutation of c.459dupA in CHRNG that predicts p.Val154SerfsX24. "
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    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.
    Preview · Article · Mar 2012 · Taiwanese journal of obstetrics & gynecology
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