Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : further insights into the phenotypic spectrum and pathogenic mechanisms
- Author
- Marlies Colman (UGent) , Robin Vroman (UGent) , Tibbe Dhooge, Zoë Malfait (UGent) , Sofie Symoens (UGent) , Biruté Burnyté, Sheela Nampoothiri, Ariana Kariminejad, Fransiska Malfait (UGent) and Delfien Syx (UGent)
- Organization
- Project
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- An integrated translational platform to improve the management and outcome of rare heritable connective tissue disease
- Understanding human linkeropathies: study of the phenotypic and molecular consequences of defective biosynthesis of the glycosaminoglycan tetrasaccharide linker region.
- Chronic pain in Ehlers-Danlos syndrome: clinical and molecular characterization in human patients and a murine model
- Identifying a pain signature in classical Ehlers-Danlos syndrome
- Linking extracellular matrix defects and chronic pain: the Ehlers-Danlos syndrome as a disease model
- An integrated translational platform to gain insights in and improve diagnosis and management of the Ehlers-Danlos Syndromes.
- Abstract
- The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue diseases. The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross-linking; or the peptidyl-prolyl cis-trans isomerase family FK506-binding protein 22 kDa (FKBP22 encoded by FKBP14), a molecular chaperone of types III, IV, VI, and X collagen. This study reports the clinical manifestations of three probands with homozygous pathogenic FKBP14 variants, including the previously reported c.362dupC; p.(Glu122Argfs*7) variant, a novel missense variant (c.587A>G; p.(Asp196Gly)) and a start codon variant (c.2T>G; p.?). Consistent clinical features in the hitherto reported individuals (n = 40) are kyphoscoliosis, generalized joint hypermobility and congenital muscle hypotonia. Severe vascular complications have been observed in 12.5%. A previously unreported feature is microcornea observed in two probands reported here. Both the c.587A>G and the c.362dupC variant cause complete loss of FKBP22. With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS-FKBP14. Scratch wound assays were largely normal. Western blot of proteins involved in the unfolded protein response and autophagy did not reveal significant upregulation in dermal fibroblasts.
- Keywords
- Genetics (clinical), Genetics, kyphoscoliotic EDS, FKBP22, extracellular matrix, Ehlers-Danlos syndrome, connective tissue, collagen
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8770419
- MLA
- Colman, Marlies, et al. “Kyphoscoliotic Ehlers‐Danlos Syndrome Caused by Pathogenic Variants in FKBP14 : Further Insights into the Phenotypic Spectrum and Pathogenic Mechanisms.” HUMAN MUTATION, vol. 43, no. 12, 2022, pp. 1994–2009, doi:10.1002/humu.24456.
- APA
- Colman, M., Vroman, R., Dhooge, T., Malfait, Z., Symoens, S., Burnyté, B., … Syx, D. (2022). Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : further insights into the phenotypic spectrum and pathogenic mechanisms. HUMAN MUTATION, 43(12), 1994–2009. https://doi.org/10.1002/humu.24456
- Chicago author-date
- Colman, Marlies, Robin Vroman, Tibbe Dhooge, Zoë Malfait, Sofie Symoens, Biruté Burnyté, Sheela Nampoothiri, Ariana Kariminejad, Fransiska Malfait, and Delfien Syx. 2022. “Kyphoscoliotic Ehlers‐Danlos Syndrome Caused by Pathogenic Variants in FKBP14 : Further Insights into the Phenotypic Spectrum and Pathogenic Mechanisms.” HUMAN MUTATION 43 (12): 1994–2009. https://doi.org/10.1002/humu.24456.
- Chicago author-date (all authors)
- Colman, Marlies, Robin Vroman, Tibbe Dhooge, Zoë Malfait, Sofie Symoens, Biruté Burnyté, Sheela Nampoothiri, Ariana Kariminejad, Fransiska Malfait, and Delfien Syx. 2022. “Kyphoscoliotic Ehlers‐Danlos Syndrome Caused by Pathogenic Variants in FKBP14 : Further Insights into the Phenotypic Spectrum and Pathogenic Mechanisms.” HUMAN MUTATION 43 (12): 1994–2009. doi:10.1002/humu.24456.
- Vancouver
- 1.Colman M, Vroman R, Dhooge T, Malfait Z, Symoens S, Burnyté B, et al. Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : further insights into the phenotypic spectrum and pathogenic mechanisms. HUMAN MUTATION. 2022;43(12):1994–2009.
- IEEE
- [1]M. Colman et al., “Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : further insights into the phenotypic spectrum and pathogenic mechanisms,” HUMAN MUTATION, vol. 43, no. 12, pp. 1994–2009, 2022.
@article{8770419,
abstract = {{The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue diseases. The autosomal recessive kyphoscoliotic EDS results from deficiency of either lysyl hydroxylase 1 (encoded by PLOD1), crucial for collagen cross-linking; or the peptidyl-prolyl cis-trans isomerase family FK506-binding protein 22 kDa (FKBP22 encoded by FKBP14), a molecular chaperone of types III, IV, VI, and X collagen. This study reports the clinical manifestations of three probands with homozygous pathogenic FKBP14 variants, including the previously reported c.362dupC; p.(Glu122Argfs*7) variant, a novel missense variant (c.587A>G; p.(Asp196Gly)) and a start codon variant (c.2T>G; p.?). Consistent clinical features in the hitherto reported individuals (n = 40) are kyphoscoliosis, generalized joint hypermobility and congenital muscle hypotonia. Severe vascular complications have been observed in 12.5%. A previously unreported feature is microcornea observed in two probands reported here. Both the c.587A>G and the c.362dupC variant cause complete loss of FKBP22. With immunocytochemistry on dermal fibroblasts, we provide the first evidence for intracellular retention of types III and VI collagen in EDS-FKBP14. Scratch wound assays were largely normal. Western blot of proteins involved in the unfolded protein response and autophagy did not reveal significant upregulation in dermal fibroblasts.}},
author = {{Colman, Marlies and Vroman, Robin and Dhooge, Tibbe and Malfait, Zoë and Symoens, Sofie and Burnyté, Biruté and Nampoothiri, Sheela and Kariminejad, Ariana and Malfait, Fransiska and Syx, Delfien}},
issn = {{1059-7794}},
journal = {{HUMAN MUTATION}},
keywords = {{Genetics (clinical),Genetics,kyphoscoliotic EDS,FKBP22,extracellular matrix,Ehlers-Danlos syndrome,connective tissue,collagen}},
language = {{eng}},
number = {{12}},
pages = {{1994--2009}},
title = {{Kyphoscoliotic Ehlers‐Danlos syndrome caused by pathogenic variants in FKBP14 : further insights into the phenotypic spectrum and pathogenic mechanisms}},
url = {{http://doi.org/10.1002/humu.24456}},
volume = {{43}},
year = {{2022}},
}
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