HGNC Approved Gene Symbol: FKBP14
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38) : 7:30,005,923-30,026,702 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p14.3 | Ehlers-Danlos syndrome, kyphoscoliotic type, 2 | 614557 | Autosomal recessive | 3 |
For background information on FK506-binding proteins (FKBPs), see FKBP1A (186945).
Baumann et al. (2012) stated that the 22-kD FKBP14 protein contains a peptidyl-prolyl isomerase domain, 2 EF-hand motifs, and an endoplasmic reticulum (ER) retention signal. They confirmed that FKBP14 is an ER-resident protein.
Baumann et al. (2012) stated that the FKBP14 gene maps to chromosome 7p15.1.
In 5 patients from 4 families with Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKSCL2; 614557), Baumann et al. (2012) identified homozygosity for a 1-bp duplication in the FKBP14 gene (c.362dupC; 614505.0001). Analysis of FKBP14 in an additional unrelated patient revealed compound heterozygosity for c.362dupC and a 19-bp deletion (614505.0002). Electron microscopy of patient fibroblasts showed dilated cisterns filled with flocculent material, and immunofluorescence experiments demonstrated disturbed distribution and assembly of several extracellular matrix (ECM) components, including collagens, type I and type III, and fibronectin as well as their receptors. Baumann et al. (2012) suggested that FKBP14 might act on one or more components of the ECM.
In a 3-year-old boy with Ehlers-Danlos syndrome and myopathy, Aldeeri et al. (2014) performed exome sequencing and identified homozygosity for a 4-bp splice site deletion in the FKBP14 gene (614505.0003).
In an 8-year-old Italian boy with EDSKSCL, Dordoni et al. (2016) sequenced the FKBP14 gene and identified compound heterozygosity for the recurrent c.362dupC mutation and a 3-bp deletion (614505.0004).
By sequencing genes in a targeted panel for Ehlers-Danlos syndrome, Castori et al. (2019) identified homozygosity for the recurrent c.362dupC mutation in the FKBP14 gene in a 15-year-old girl with EDSKSCL who showed severe involvement of the lower limb muscles. Her unaffected parents were heterozygous for the mutation.
In 5 patients with Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKSCL2; 614557) from 4 unrelated families of Austrian, Italian, French, and Turkish origin, Baumann et al. (2012) identified homozygosity for a 1-bp duplication within a 5C-nucleotide repeat in exon 3 (c.362dupC, NM_017946.2) of the FKBP14 gene, causing a frameshift predicted to result in a premature termination codon (Glu122ArgfsTer7). Western blot analysis demonstrated absence of FKBP14 in patient fibroblasts, and qRT-PCR analysis showed strongly reduced FKBP14 expression compared to controls, consistent with nonsense-mediated decay. In an unrelated patient with EDSKMH, Baumann et al. (2012) identified compound heterozygosity for the 362dupC mutation and a 19-bp deletion (42_60del) in exon 1 of the FKBP14 gene (614505.0002), also predicted to result in a premature termination codon. The 362dupC mutation was linked to the same haplotype in all individuals, despite their geographically diverse origins, suggesting a possible founder event. Neither mutation was found in 200 controls of European descent.
In an 8-year-old Italian boy with EDSKSCL, Dordoni et al. (2016) identified compound heterozygosity for the recurrent c.362dupC mutation in exon 3 of the FKBP14 gene, and an in-frame 3-bp deletion (c.573_575del; 614505.0004) in exon 4, causing deletion of 1 residue (Glu191del). His unaffected parents were each heterozygous for 1 of the mutations.
By sequencing of genes in a targeted panel for Ehlers-Danlos syndrome, Castori et al. (2019) identified homozygosity for the recurrent c.362dupC mutation in the FKBP14 gene in a 15-year-old girl with EDSKSCL who showed severe involvement of the lower limb muscles. Her unaffected parents were heterozygous for the mutation.
For discussion of the 19-bp deletion in the FKBP14 gene (c.42_60del, NM_017946.2) that was found in compound heterozygous state in a patient with Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKSCL2; 614557) by Baumann et al. (2012), see 614505.0001.
In a 3-year-old boy with Ehlers-Danlos syndrome and myopathy (EDSKSCL2; 614557), Aldeeri et al. (2014) identified homozygosity for a 4-bp splice site deletion (c.197+5_197+8delGTAA, NM_017946.3) in the FKBP14 gene. No specific mention was made of kyphoscoliosis or hearing loss, but the child had a 'waddling gait' and 'only 50% of his speech was understandable by strangers.' No hearing test was reported.
For discussion of the 3-bp deletion (c.573_575del, NM_017946.3) in exon 4 of the FKBP14 gene, resulting in deletion of 1 residue (Glu191del), that was found in compound heterozygous state in an 8-year-old Italian boy with the kyphoscoliotic type of Ehlers-Danlos syndrome (EDSKSCL2; 614557) by Dordoni et al. (2016), see 614505.0001. The mutation was referred to as c.573_576del in the text of the report and as c.573_575del in Figure 2.
Aldeeri, A. A., Alazami, A. M., Hijazi, H., Alzahrani, F., Alkuraya, F. S. Excessively redundant umbilical skin as a potential early clinical feature of Morquio syndrome and FKBP14-related Ehlers-Danlos syndrome. Clin. Genet. 86: 469-472, 2014. [PubMed: 24773188] [Full Text: https://doi.org/10.1111/cge.12414]
Baumann, M., Giunta, C., Krabichler, B., Ruschendorf, F., Zoppi, N., Colombi, M., Bittner, R. E., Quijano-Roy, S., Muntoni, F., Cirak, S., Schreiber, G., Zou, Y., and 13 others. Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am. J. Hum. Genet. 90: 201-216, 2012. [PubMed: 22265013] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.004]
Castori, M., Fiorillo, C., Agolini, E., Sacco, M., Minetti, C., Novelli, A., Guglielmi, G., Bertini, E. Primary muscle involvement in a 15-year-old girl with the recurrent homozygous c.362dupC variant in FKBP14. Am. J. Med. Genet. 179 317-321, 2019. [PubMed: 30561154] [Full Text: https://doi.org/10.1002/ajmg.a.61006]
Dordoni, C., Ciaccio, C., Venturini, M., Calzavara-Pinton, P., Ritelli, M., Colombi, M. Further delineation of FKBP14-related Ehlers-Danlos syndrome: a patient with early vascular complications and non-progressive kyphoscoliosis, and literature review. Am. J. Med. Genet. 170A: 2031-2038, 2016. [PubMed: 27149304] [Full Text: https://doi.org/10.1002/ajmg.a.37728]