Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 12;14(4):472.
doi: 10.3390/biom14040472.

Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review

Raquel Pliego-Arreaga  1 , Juan Antonio Cervantes-Montelongo  1   2 , Guillermo Antonio Silva-Martínez  2 , Fabiola Estefanía Tristán-Flores  3 , Miguel Angel Pantoja-Hernández  1 , Juan Raúl Maldonado-Coronado  1
Affiliations
Review

Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review

Raquel Pliego-Arreaga et al. Biomolecules. .

Abstract

Ehlers-Danlos syndromes (EDSs) constitute a heterogeneous group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Asymptomatic EDSs, joint hypermobility without associated syndromes, EDSs, and hypermobility spectrum disorders are the commonest phenotypes associated with joint hypermobility. Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by extreme flexibility of the joints, along with pain and other symptoms. JHS can be a sign of a more serious underlying genetic condition, such as EDS, which affects the cartilage, bone, fat, and blood. The exact cause of JHS could be related to genetic changes in the proteins that add flexibility and strength to the joints, ligaments, and tendons, such as collagen. Membrane proteins are a class of proteins embedded in the cell membrane and play a crucial role in cell signaling, transport, and adhesion. Dysregulated membrane proteins have been implicated in a variety of diseases, including cancer, cardiovascular disease, and neurological disorders; recent studies have suggested that membrane proteins may also play a role in the pathogenesis of JHS. This article presents an exploration of the causative factors contributing to musculoskeletal pain in individuals with hypermobility, based on research findings. It aims to provide an understanding of JHS and its association with membrane proteins, addressing the clinical manifestations, pathogenesis, diagnosis, and management of JHS.

Keywords: Ehlers–Danlos syndrome; joint hypermobility syndrome; membrane proteins in joint hypermobility.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Mutations in collagen genes and their impact on collagen fibrils: Mutations identified in collagen genes such as COL3A1, COL5A1, and COL5A2 have been associated with JHS. These mutations impact the structure of collagen fibrils, changing from a normal distribution and shape (a) to abnormal morphologies: cauliflower-like (b) or acquiring a variable diameter and irregular spacing (c).
Figure 2
Figure 2
Molecular basis of folate-dependent hypermobility syndrome: MTHFR polymorphisms C677T and A1298C reduce or increase serum folate levels, respectively. High levels of folate increase methylation of the MMP2 gene, leading to low levels of the protein, decreasing cleavage of decorin, disrupting collagen organization, and causing tissue instability and fragility. Additionally, low levels of MMP2 trigger aberrant TGF-ß signaling, initiating fibrotic pathways. Dihydrofolic acid (DHF); Tetrahydrofolate (THF); 5,10-Methylenetetrahydrofolate (5,10-MTHF); Methylenetetrahydrofolate reductase (MTHFR); 5-methyltetrahydrofolate (5-MTHF); S-adenosylmethionine (SAM); Matrix Metalloproteinase 2 (MMP2); Transforming growth factor-β (TGF-β).
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Grahame R. Joint Hypermobility and Genetic Collagen Disorders: Are They Related? Arch. Dis. Child. 1999;80:188–191. doi: 10.1136/adc.80.2.188. - DOI - PMC - PubMed
    1. Malfait F., Hakim A.J., De Paepe A., Grahame R. The Genetic Basis of the Joint Hypermobility Syndromes. Rheumatology. 2006;45:502–507. doi: 10.1093/rheumatology/kei268. - DOI - PubMed
    1. Castori M., Morlino S., Celletti C., Ghibellini G., Bruschini M., Grammatico P., Blundo C., Camerota F. Re-writing the Natural History of Pain and Related Symptoms in the Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome, Hypermobility Type. Am. J. Med. Genet. Part A Semin. Med. Genet. 2013;161:2989–3004. doi: 10.1002/ajmg.a.36315. - DOI - PubMed
    1. Tinkle B.T., Levy H.P. Symptomatic Joint Hypermobility. Med. Clin. N. Am. 2019;103:1021–1033. doi: 10.1016/j.mcna.2019.08.002. - DOI - PubMed
    1. Remvig L., Jensen D.V., Ward R.C. Epidemiology of general joint hypermobility and basis for the proposed criteria for benign joint hypermobility syndrome: Review of the literature. J. Rheumatol. 2007;34:804–809. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

We thank to Universidad de Celaya for the support in the realization of this manuscript.