Background While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55–200 repeats) of the FMR1 gene may be overlooked.
Objective To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.
Methods We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.
Results Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity.
Conclusion Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.
- genetic predisposition to disease
- human genetics
- gene expression
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Contributors RH, ELC and NT made substantial contributions to the conception of the work. RH, ELC, NT, EM, KN and ICP drafted the manuscript. RH, ELC, CBB and CR wrote case histories. FMcK, FT and PH wrote the Methods section. FT, MJJ and PH did the molecular analysis and provided the results. NT and ELC wrote the Discussion. FMcK, YAMcL, EM, FT, RH and ELC made critical revisions. RH, ELC and CBB made substantial contributions to funding, patient recruitment and ascertainment, and data collection. All authors approved the submitted version of the manuscript.
Funding This study was funded by NICHD HD036071, the Tides Foundation, the MIND Institute IDDRC (grant U54 HD079125), and the National Centre for Advancing Translational Sciences and National Institutes of Health (grant UL1 TR001860).
Competing interests FT has received from Azrieli Foundation, from Zynerba and from Asuragen, Inc. for studies in fragile X syndrome.
Provenance and peer review Not commissioned; externally peer reviewed.
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