A cohort of 17 patients with kyphoscoliotic Ehlers–Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history

Abstract

Purpose: In 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic EhlersDanlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date. Methods:We report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.Results: Based on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals. Conclusion:Our data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions

“…Here we show that a partial loss of function leads to a similar phenotype as the complete loss of FKBP22 even though M48K FKBP22 could still have fully functional EF hand motifs, the function of which is mostly unknown except for binding calcium 30,31 . The molecular findings are in keeping with the clinical findings of the homozygous M48K patient which were similar to these of FKBP22 null patients 7 . In summary, our study provides direct evidence for the effects of the M48K mutation in FKBP22, however additional studies are required to explore the disease mechanism of FKBP14-kEDS.…”

“…A novel homozygous c.143 T > A substitution in exon 1 in FKBP14 replaces Met 48 residue with a Lys residue in FKBP22 protein and causes kEDS 7 . In contrast to the other known mutations in FKBP14, the M48K FKBP22 transcript is efficiently translated and does not undergo nonsense-mediated mRNA decay.…”

“…(2020) 10:497 | https://doi.org/10.1038/s41598-019-57374-y www.nature.com/scientificreports www.nature.com/scientificreports/ of patients with FKBP14-kEDS suffer from refraction anomalies 7 . On the other hand, muscular impairment is identified in almost 100% of patients 7 . Such tissue specific differences could be attributed to the different binding affinities of FKBP22 to individual collagens since tissues differ in their collagen makeup.…”

“…homozygous c.143 T > A substitution in exon 1 of FKBP14 6,7 , that is predicted to produce an FKBP22 protein with a Met48Lys (M48K).…”

Síndrome de Ehlers-Danlos cifoescoliótico-FKBP14 en una paciente adolescente: primer reporte de caso colombiano

“…Este subtipo ha sido, generalmente, asociado con mutaciones en homocigosis del gen PLOD1, que codifica la enzima lisil hidroxilasa; sin embargo, desde su primera descripción en 2012, 6 algunos casos con mutaciones en homocigosis o heterocigotos compuestos en el gen FKBP14 han sido reportados en la literatura para esta forma de EDS. [9][10][11][12][13] Aldeeri y col., en 2014, publicaron el caso de un niño de 3 años de edad con un fenotipo leve y una nueva mutación homocigota del sitio de splicing en FKBP14. Debido a la presencia de tejido redundante umbilical (ombligo cutáneo) en el paciente, ellos propusieron este signo como un potencial hallazgo clínico temprano para el diagnóstico de esta enfermedad.…”