Genetic Conditions Affecting the Skeleton: Congenital, Idiopathic Scoliosis and Arthrogryposis

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (16 May 2021) | Viewed by 41943

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Special Issue Editors


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Guest Editor
University of Illinois-Chicago, Chicago, IL 60607, USA
Interests: genetics of congenital scoliosis; idiopathic scoliosis and vertebral malformations

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Guest Editor
Children's Hospital Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Interests: genetics of idiopathic scoliosis

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Guest Editor
Hospital for Special Surgery, New York, NY 10021, USA
Interests: genetics of congenital and idiopathic scoliosis; osteogenesis imperfecta

Special Issue Information

Although uniquely occurring conditions, congenital scoliosis, idiopathic scoliosis, and arthrogryposis share overlapping phenotypic features and potentially etiopathogenic mechanisms. Congenital scoliosis (CS) is defined by the presence of an abnormal spinal curvature due to an underlying vertebral bony malformation (VM). Idiopathic scoliosis (IS) is defined by the presence of an abnormal structural spinal curvature of >/=10 degrees in the sagittal plane in the absence of an underlying VM. Arthrogryposis is defined by the presence of congenital contractures in two or more joints of the appendicular skeleton. Scoliosis with or without vertebral malformations may occur in association with arthrogryposis. Congenital scoliosis, idiopathic scoliosis, vertebral malformation, and arthrogryposis may be caused by mutations in genes which code for connective tissue matrix proteins. The search for genes and pathways is ongoing and may lead to potential therapies. In this issue, we will review what is currently known about genetic contributions associated with these conditions, discuss how genetics has or may contribute to potential therapies, and help to identify prognostic indicators.

Keywords

  • Congenital scoliosis 
  • Idiopathic scoliosis 
  • Arthrogryposis 
  • Genetics 
  • Vertebral malformation 
  • Neuromuscular 
  • Transcriptome 
  • Next-generation sequence analysis

Published Papers (12 papers)

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Editorial

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3 pages, 179 KiB  
Editorial
Overview of Gene Special Issue “Genetic Conditions Affecting the Skeleton: Congenital, Idiopathic Scoliosis and Arthrogryposis”
by Philip F. Giampietro, Nancy Hadley-Miller and Cathy L. Raggio
Genes 2022, 13(7), 1194; https://doi.org/10.3390/genes13071194 - 4 Jul 2022
Cited by 3 | Viewed by 2570
Abstract
In this Special Issue of Genes entitled “Genetic Conditions Affecting the Skeleton: Congenital, Idiopathic Scoliosis and Arthrogryposis”, evidence is presented which suggests that congenital, idiopathic scoliosis, and arthrogryposis share similar overlapping, but also distinct etiopathogenic mechanisms, including connective tissue and neuromuscular mechanisms [...] [...] Read more.
In this Special Issue of Genes entitled “Genetic Conditions Affecting the Skeleton: Congenital, Idiopathic Scoliosis and Arthrogryposis”, evidence is presented which suggests that congenital, idiopathic scoliosis, and arthrogryposis share similar overlapping, but also distinct etiopathogenic mechanisms, including connective tissue and neuromuscular mechanisms [...] Full article

Research

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12 pages, 1596 KiB  
Article
The Mutational Landscape of PTK7 in Congenital Scoliosis and Adolescent Idiopathic Scoliosis
by Zhe Su, Yang Yang, Shengru Wang, Sen Zhao, Hengqiang Zhao, Xiaoxin Li, Yuchen Niu, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) Study Group, Guixing Qiu, Zhihong Wu, Nan Wu and Terry Jianguo Zhang
Genes 2021, 12(11), 1791; https://doi.org/10.3390/genes12111791 - 12 Nov 2021
Cited by 5 | Viewed by 2360
Abstract
Depletion of ptk7 is associated with both congenital scoliosis (CS) and adolescent idiopathic scoliosis (AIS) in zebrafish models. However, only one human variant of PTK7 has been reported previously in a patient with AIS. In this study, we systemically investigated the variant landscape [...] Read more.
Depletion of ptk7 is associated with both congenital scoliosis (CS) and adolescent idiopathic scoliosis (AIS) in zebrafish models. However, only one human variant of PTK7 has been reported previously in a patient with AIS. In this study, we systemically investigated the variant landscape of PTK7 in 583 patients with CS and 302 patients with AIS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study. We identified a total of four rare variants in CS and four variants in AIS, including one protein truncating variant (c.464_465delAC) in a patient with CS. We then explored the effects of these variants on protein expression and sub-cellular location. We confirmed that the c.464_465delAC variant causes loss-of-function (LoF) of PTK7. In addition, the c.353C>T and c.2290G>A variants identified in two patients with AIS led to reduced protein expression of PTK7 as compared to that of the wild type. In conclusion, LoF and hypomorphic variants are associated with CS and AIS, respectively. Full article
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14 pages, 6041 KiB  
Article
The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children
by Noémi Dahan-Oliel, Klaus Dieterich, Frank Rauch, Ghalib Bardai, Taylor N. Blondell, Anxhela Gjyshi Gustafson, Reggie Hamdy, Xenia Latypova, Kamran Shazand, Philip F. Giampietro and Harold van Bosse
Genes 2021, 12(8), 1220; https://doi.org/10.3390/genes12081220 - 6 Aug 2021
Cited by 5 | Viewed by 4464
Abstract
Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and [...] Read more.
Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up and orthopedic management. Methods: Retrospective chart review and prospective data collection were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome or whole genome sequencing. Results: This case series describes the clinical features and scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven; two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. The remaining 11 patients spanned the spectrum between mild (curve ≤ 25°) and malignant scoliosis (≥50° curve before 4 years of age); the two patients with MYH3 mutations presented with malignant scoliosis. Bracing and serial spine casting appear to be beneficial for a few years; non-fusion spinal instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of the spine is needed in children with MPS. Full article
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12 pages, 2374 KiB  
Article
Identification of Copy Number Variants in a Southern Chinese Cohort of Patients with Congenital Scoliosis
by Wenjing Lai, Xin Feng, Ming Yue, Prudence W. H. Cheung, Vanessa N. T. Choi, You-Qiang Song, Keith D. K. Luk, Jason Pui Yin Cheung and Bo Gao
Genes 2021, 12(8), 1213; https://doi.org/10.3390/genes12081213 - 5 Aug 2021
Cited by 6 | Viewed by 3710
Abstract
Congenital scoliosis (CS) is a lateral curvature of the spine resulting from congenital vertebral malformations (CVMs) and affects 0.5–1/1000 live births. The copy number variant (CNV) at chromosome 16p11.2 has been implicated in CVMs and recent studies identified a compound heterozygosity of 16p11.2 [...] Read more.
Congenital scoliosis (CS) is a lateral curvature of the spine resulting from congenital vertebral malformations (CVMs) and affects 0.5–1/1000 live births. The copy number variant (CNV) at chromosome 16p11.2 has been implicated in CVMs and recent studies identified a compound heterozygosity of 16p11.2 microdeletion and TBX6 variant/haplotype causing CS in multiple cohorts, which explains about 5–10% of the affected cases. Here, we studied the genetic etiology of CS by analyzing CNVs in a cohort of 67 patients with congenital hemivertebrae and 125 family controls. We employed both candidate gene and family-based approaches to filter CNVs called from whole exome sequencing data. This identified 12 CNVs in four scoliosis-associated genes (TBX6, NOTCH2, DSCAM, and SNTG1) as well as eight recessive and 64 novel rare CNVs in 15 additional genes. Some candidates, such as DHX40, NBPF20, RASA2, and MYSM1, have been found to be associated with syndromes with scoliosis or implicated in bone/spine development. In particular, the MYSM1 mutant mouse showed spinal deformities. Our findings suggest that, in addition to the 16p11.2 microdeletion, other CNVs are potentially important in predisposing to CS. Full article
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20 pages, 10462 KiB  
Article
Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis
by Patrick M. Carry, Elizabeth A. Terhune, George D. Trahan, Lauren A. Vanderlinden, Cambria I. Wethey, Parvaneh Ebrahimi, Fiona McGuigan, Kristina Åkesson and Nancy Hadley-Miller
Genes 2021, 12(8), 1191; https://doi.org/10.3390/genes12081191 - 30 Jul 2021
Cited by 8 | Viewed by 3163
Abstract
Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. [...] Read more.
Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS. Full article
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11 pages, 2342 KiB  
Article
Novel FGFR1 Variants Are Associated with Congenital Scoliosis
by Shengru Wang, Xiran Chai, Zihui Yan, Sen Zhao, Yang Yang, Xiaoxin Li, Yuchen Niu, Guanfeng Lin, Zhe Su, Zhihong Wu, Terry Jianguo Zhang and Nan Wu
Genes 2021, 12(8), 1126; https://doi.org/10.3390/genes12081126 - 24 Jul 2021
Cited by 3 | Viewed by 3722
Abstract
FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. [...] Read more.
FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring FGFR1 variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) FGFR1. As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, FGFR1 variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously. Full article
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19 pages, 3910 KiB  
Article
A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita
by Xenia Latypova, Stefan Giovanni Creadore, Noémi Dahan-Oliel, Anxhela Gjyshi Gustafson, Steven Wei-Hung Hwang, Tanya Bedard, Kamran Shazand, Harold J. P. van Bosse, Philip F. Giampietro and Klaus Dieterich
Genes 2021, 12(7), 1052; https://doi.org/10.3390/genes12071052 - 8 Jul 2021
Cited by 3 | Viewed by 3442
Abstract
Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% [...] Read more.
Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs). Upon query, we identified only two patients with both AMC and scoliosis (AMC-SC). The first patient contained CNVs in three genes (FBN2, MGF10, and PITX1), while the second case had a CNV in ZC4H2. Looking into small variants, using a combination of Human Phenotype Ontogeny and literature searching, 908 genes linked with scoliosis and 444 genes linked with AMC were identified. From these lists, 227 genes were associated with AMC-SC. Ingenuity Pathway Analysis (IPA) was performed on the final gene list to gain insight into the functional interactions of genes and various categories. To summarize, this group of genes encompasses a diverse group of cellular functions including transcription regulation, transmembrane receptor, growth factor, and ion channels. These results provide a focal point for further research using genomics and animal models to facilitate the identification of prognostic factors and therapeutic targets for AMC. Full article
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8 pages, 1571 KiB  
Article
Prevalence of POC5 Coding Variants in French-Canadian and British AIS Cohort
by Hélène Mathieu, Aurélia Spataru, José Antonio Aragon-Martin, Anne Child, Soraya Barchi, Carole Fortin, Stefan Parent and Florina Moldovan
Genes 2021, 12(7), 1032; https://doi.org/10.3390/genes12071032 - 1 Jul 2021
Cited by 4 | Viewed by 2214
Abstract
Adolescent idiopathic scoliosis (AIS) is a complex common disorder of multifactorial etiology defined by a deviation of the spine in three dimensions that affects approximately 2% to 4% of adolescents. Risk factors include other affected family members, suggesting a genetic component to the [...] Read more.
Adolescent idiopathic scoliosis (AIS) is a complex common disorder of multifactorial etiology defined by a deviation of the spine in three dimensions that affects approximately 2% to 4% of adolescents. Risk factors include other affected family members, suggesting a genetic component to the disease. The POC5 gene was identified as one of the first ciliary candidate genes for AIS, as three variants were identified in large families with multiple members affected with idiopathic scoliosis. To assess the prevalence of p.(A429V), p.(A446T), and p.(A455P) POC5 variants in patients with AIS, we used next-generation sequencing in our cohort of French-Canadian and British families and sporadic cases. Our study highlighted a prevalence of 13% for POC5 variants, 7.5% for p.(A429V), and 6.4% for p.(A446T). These results suggest a higher prevalence of the aforementioned POC5 coding variants in patients with AIS compared to the general population. Full article
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15 pages, 1738 KiB  
Article
Whole Exome Sequencing of 23 Multigeneration Idiopathic Scoliosis Families Reveals Enrichments in Cytoskeletal Variants, Suggests Highly Polygenic Disease
by Elizabeth A. Terhune, Cambria I. Wethey, Melissa T. Cuevas, Anna M. Monley, Erin E. Baschal, Morgan R. Bland, Robin Baschal, G. Devon Trahan, Matthew R. G. Taylor, Kenneth L. Jones and Nancy Hadley Miller
Genes 2021, 12(6), 922; https://doi.org/10.3390/genes12060922 - 16 Jun 2021
Cited by 9 | Viewed by 3560
Abstract
Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature >10° with rotation that affects 2–3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and [...] Read more.
Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature >10° with rotation that affects 2–3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and next-generation sequencing methods, the underlying etiology of the condition remains largely unknown. In this study, we performed exome sequencing of affected individuals within 23 multigenerational families, with the hypothesis that the occurrence of rare, low frequency, disease-causing variants will co-occur in distantly related, affected individuals. Bioinformatic filtering of uncommon, potentially damaging variants shared by all sequenced family members revealed 1448 variants in 1160 genes across the 23 families, with 132 genes shared by two or more families. Ten genes were shared by >4 families, and no genes were shared by all. Gene enrichment analysis showed an enrichment of variants in cytoskeletal and extracellular matrix related processes. These data support a model that AIS is a highly polygenic disease, with few variant-containing genes shared between affected individuals across different family lineages. This work presents a novel resource for further exploration in familial AIS genetic research. Full article
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15 pages, 3307 KiB  
Article
Methylation of Estrogen Receptor 1 Gene in the Paraspinal Muscles of Girls with Idiopathic Scoliosis and Its Association with Disease Severity
by Piotr Janusz, Małgorzata Chmielewska, Mirosław Andrusiewicz, Małgorzata Kotwicka and Tomasz Kotwicki
Genes 2021, 12(6), 790; https://doi.org/10.3390/genes12060790 - 21 May 2021
Cited by 14 | Viewed by 2656
Abstract
Idiopathic scoliosis (IS) is a multifactorial disease with epigenetic modifications. Tissue dependent and differentially methylated regions (T-DMRs) may regulate tissue-specific expression of the estrogen receptor 1 gene (ESR1). This study aimed to analyze methylation levels within T-DMR1 and T-DMR2 and its [...] Read more.
Idiopathic scoliosis (IS) is a multifactorial disease with epigenetic modifications. Tissue dependent and differentially methylated regions (T-DMRs) may regulate tissue-specific expression of the estrogen receptor 1 gene (ESR1). This study aimed to analyze methylation levels within T-DMR1 and T-DMR2 and its concatenation with ESR1 expression of IS patients. The study involved 87 tissue samples (deep paravertebral muscles, both on the convex and the concave side of the curve, and from back superficial muscles) from 29 girls who underwent an operation due to IS. Patient subgroups were analyzed according to Cobb angle ≤70° vs. >70°. Methylation was significantly higher in the superficial muscles than in deep paravertebral muscles in half of the T-DMR1 CpGs and all T-DMR2 CpGs. The methylation level correlated with ESR1 expression level on the concave, but not convex, side of the curvature in a majority of the T-DMR2 CpGs. The T-DMR2 methylation level in the deep paravertebral muscles on the curvature’s concave side was significantly lower in patients with a Cobb angle ≤70° in four CpGs. DNA methylation of the T-DMRs is specific to muscle tissue location and may be related to ESR1 expression regulation. Additionally, the difference in T-DMR2 methylation may be associated with IS severity. Full article
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Review

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15 pages, 4703 KiB  
Review
A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait—A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis
by Nelson L. S. Tang, Matthew B. Dobbs, Christina A. Gurnett, Yong Qiu, T. P. Lam, Jack C. Y. Cheng and Nancy Hadley-Miller
Genes 2021, 12(7), 1033; https://doi.org/10.3390/genes12071033 - 1 Jul 2021
Cited by 7 | Viewed by 5327
Abstract
Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in [...] Read more.
Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model for AIS. Here, we review in detail the vast information about the genetic and environmental factors in AIS pathogenesis gathered to date. More importantly, new insights into AIS etiology were brought to us through new research data under the perspective of a complex trait. Hopefully, future research directions may lead to better management of AIS, which has a tremendous impact on affected adolescents in terms of both physical growth and psychological development. Full article
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14 pages, 1243 KiB  
Review
Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome
by Julia Whittle, Aaron Johnson, Matthew B. Dobbs and Christina A. Gurnett
Genes 2021, 12(6), 943; https://doi.org/10.3390/genes12060943 - 20 Jun 2021
Cited by 7 | Viewed by 2867
Abstract
Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including [...] Read more.
Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice. Full article
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