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FK506-BINDING PROTEIN 10; FKBP10

FK506-BINDING PROTEIN 10; FKBP10

Alternative titles; symbolsFKBP65HGNC Approved Gene Symbol: FKBP10Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,812,937-41,823,214 (from ...

Alternative titles; symbols

  • FKBP65

HGNC Approved Gene Symbol: FKBP10

Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,812,937-41,823,214 (from NCBI)

▼ Description
FKBP10 (FKBP65) is a member of a group of proteins termed immunophilins, which were initially identified by their high binding affinity for the immunosuppressant drugs cyclosporin A (CsA) and FK506. Based on their ability to bind either one of these 2 drugs, 2 structurally distinct subfamilies of immunophilins emerged: the cyclophilins (see, e.g., 123840) and the FK506-binding proteins, such as FKBP10. All immunophilins possess the protein folding property of peptidyl-prolyl cis-trans isomerization (summary by Patterson et al., 2000). FKBP10 is thought to function as a collagen chaperone and to assist in collagen folding (Lietman et al., 2014).

▼ Cloning and Expression
Patterson et al. (2000) found that mouse Fkbp10 is contained within the lumen of the endoplasmic reticulum (ER). Western blot analysis detected expression in 12-day-old mouse aorta, brain, kidney, and lung; no or barely detectable expression was found in adult tissues. Immunolocalization of Fkbp10 in developing lung revealed staining of vascular and airway smooth muscle cells. Patterson et al. (2002) stated that the human and mouse protein sequences are identical with the exception of a valine-24 addition within the signal sequence of the human protein. Both contain 4 consecutive PPIase domains.

Using beta-galactosidase staining in Fkbp10 +/- mice, Lietman et al. (2014) found that Fkbp10 expression began at embryonic day 13.5 (E13.5) and increased by E15.5, with prominent expression in skeletal tissues. Expression was also detected in developing ligaments, in large vessels of the heart and lung, and in glomeruli and various renal tubular structures. When mice were 2 months of age, Fkbp10 expression was limited to bone, ligament, and tendon.

▼ Gene Structure
Patterson et al. (2002) determined that both the human and mouse FKBP10 genes contain 10 exons.

▼ Mapping
Gross (2014) mapped the FKBP10 gene to chromosome 17q21.2 based on an alignment of the FKBP10 sequence (GenBank AF337909) with the genomic sequence (GRCh38).

▼ Gene Function
Duran et al. (2015) studied whether HSP47 (SERPINH1; 600943) deficiency in patients with osteogenesis imperfecta-10 (OI10; 613848) might also affect levels or activity of FKBP65. Western blot analysis of cultured OI10 dermal fibroblasts (homozygous for an M237T mutation in SERPINH1; 600943.0003) showed an approximately 50% reduction of FKBP65 compared to control cells; in contrast, analysis of OI11 (610968) patient cells (homozygous for the FKBP10 c.831dupC null allele; 607063.0002) did not show a concomitant effect on HSP47 levels, which were similar to those of control cells. However, immunofluorescence demonstrated that unlike the reticular pattern observed in control cells, both HSP47 and FKBP65 in either FKBP65-null or HSP47-mutant cells showed a punctate staining pattern, and both proteins accumulated within large vacuolar-like structures adjacent to the endoplasmic reticulum. Proximity ligation assay in control cells showed interaction of HSP47 and FKBP65 as single dots in the cytoplasm; in HSP47-mutant cells, the number of interactions was reduced and the interactions were clustered in a narrow area. Duran et al. (2015) suggested that HSP47 and FKBP65 interact or work in very close proximity, and that abnormalities in either protein result in abnormal trafficking, which drags a significant fraction of the complex into vesicles. In further experiments, they observed that type I procollagen maintained its normal localization in the ER and Golgi in HSP47-mutant or FKBP65-null cells, but was also found in the HSP47- and FKBP65-accumulating vesicles, indicating that some type I procollagen molecules might not be processed normally and could be recycled or removed along with the defective chaperones. Duran et al. (2015) suggested that the similarity in phenotype between OI10 and OI11 might be explained by the similar consequences on type I procollagen synthesis.

▼ Molecular Genetics
In affected members of 5 consanguineous Turkish families segregating autosomal recessive epidermolysis bullosa simplex (139100) and a severe progressive form of osteogenesis imperfecta (OI11; 610968), Alanay et al. (2010) identified homozygosity for 2 mutations: a missense mutation in the KRT14 gene (148066.0006) known to cause EB simplex, and an in-frame deletion in the FKBP10 gene (607063.0001) causing OI type XI. In 3 Mexican sibs with severe progressive deforming OI, they identified homozygosity for a null mutation in the FKBP10 gene (607063.0002). Neither FKBP10 mutation was found in a panel of 210 alleles from ethnically matched unaffected individuals. The FKBP10 gene encodes a chaperone that participates in type I procollagen folding, and Alanay et al. (2010) determined that FKBP10 mutations affect type I procollagen secretion.

In 2 brothers with Bruck syndrome mapping to chromosome 17q21.2 (BRKS1; 259450), Shaheen et al. (2010) identified homozygosity for an 8-bp insertion in the FKBP10 gene (607063.0003). They suggested that the patients reported by Alanay et al. (2010) with OI may have had Bruck syndrome. Alanay and Krakow (2010) suggested that the phenotype due to mutations in the FKBP10 gene be categorized as a recessive form of progressive deforming osteogenesis with or without joint contractures.

Kelley et al. (2011) sequenced the FKBP10 gene in 6 individuals from 5 families with a moderately severe OI phenotype, 4 with joint contractures, including the patient reported by Viljoen et al. (1989), and 1 (patient 2) without congenital joint contractures, and identified homozygous or compound heterozygous mutations in all. In 2 sibs, one with and one without contractures, they identified homozygosity for a previously identified frameshift mutation (607063.0002).

Shaheen et al. (2011) described a consanguineous Saudi family in which 3 sisters and 2 male cousins had Bruck syndrome and the same novel mutation in the FKBP10 gene (743dupC; 607063.0007). Four of those affected did not have contractures; the fifth had abnormal skin folds at the popliteal area that caused flexion contractures of the knees, which were noticed at birth, and he later had frequent fractures.

Puig-Hervas et al. (2012) screened for mutations in 6 consanguineous unrelated Egyptian families with Bruck syndrome and identified homozygous mutations in the FKBP10 gene in 2 families and in the PLOD2 gene (601865) in 4 families (see BRKS2; 609220). Two probands had the same insertion/deletion mutation in the FKBP10 gene (607063.0009).

Barnes et al. (2012) identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in the FKBP10 or PPIB (123841) gene. In 1 pedigree branch, both parents carried a deletion in the PPIB gene (123841.0004) causing lethal OI type IX (OI9; 259440) in their 2 children. In the other pedigree branch, a child with moderate type XI OI was homozygous for the indel mutation in the FKBP10 gene (607063.0009) previously identified in a Bruck syndrome patient. Proband FKBP10 transcripts were 4% of control and FKBP10 protein was absent from proband cells. Proband collagen electrophoresis revealed slight band broadening, compatible with approximately 10% overmodification. Normal chain incorporation, helix folding, and collagen Tm supported a minimal general collagen chaperone role for FKBP10. However, there was a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry revealed absence of hydroxylation of the collagen telopeptide lysine involved in crosslinking, and Barnes et al. (2012) suggested that FKBP10 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Barnes et al. (2012) also suggested that FKBP10 protein may be required for activity of LH2, encoded by PLOD2 (601865), against collagen telopeptide domains. Proband collagen to organics ratio in matrix was approximately 30% of normal in Raman spectra. Immunofluorescence showed sparse, disorganized collagen fibrils in proband matrix.

Schwarze et al. (2013) identified mutations in the FKBP10 gene in 38 members of 21 families with OI, including 4 patients from 2 families diagnosed with Bruck syndrome by Bank et al. (1999) and McPherson and Clemens (1997) (see 607063.0006 and 607063.0010, respectively). Seventeen patients from 10 families originated from Samoa or nearby islands in the South Pacific and shared a founder mutation (98dupT; 607063.0011); 17 patients from 7 families were from different Middle Eastern countries; and the remaining 4 were identified in the US. Nine different mutations were identified, including 5 frameshift mutations, 3 missense mutations, and 1 nonsense mutation. The loss of the activity of FKBP10 had several effects: type I procollagen secretion was slightly delayed, the stabilization of the intact trimer was incomplete, and there was diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular crosslink formation in bone. Schwarze et al. (2013) suggested that the absence or marked diminution of FKBP10 may mediate the phenotype, at least in part, through a failure of LH2, encoded by PLOD2, to fully hydroxylate telopeptide lysines in type I collagen molecules in bone.

Using homozygosity mapping, linkage analysis, and Sanger sequencing, Barnes et al. (2013) identified a homozygous 3-bp deletion in exon 5 of the FKBP10 gene (c.877_879delTAC, Tyr293del; 607063.0012) in patients with Kuskokwim disease from multiple Kuskokwim pedigrees. Affected individuals had contractures of variable severity as well as variable skeletal manifestations, including osteopenia, scoliosis, lordosis, short stature, and low energy fractures. Three percent (3/96 alleles) of regional controls were shown to be carriers of the Tyr293del variant.

▼ Animal Model
Lietman et al. (2014) found that embryonic Fkbp10 -/- mice showed generalized tissue fragility and growth delay by E13.5. Embryos were viable at E18.5, but no viable Fkbp10 -/- mice were recovered at postnatal day 0. Fkbp10 -/- mice also showed reduced width of both ascending and descending aortic walls, but there was no major change in collagen organization and no patterning defect. Electron microscopic examination of E13.5 fibroblasts revealed ER dilation and enhanced content of autophagosomes, with accumulation of abnormal, poorly formed collagen matrix. Mutant fibroblasts also showed increased procollagen content, but they revealed only a mild delay in collagen secretion. Collagen from Fkbp10 -/- fibroblasts was more soluble than collagen from wildtype fibroblasts, with underhydroxylation of N- and C-terminal lysines, suggesting reduced telopeptide hydroxylysine-aldehyde crosslinking, similar to that found in skin collagen.

▼ ALLELIC VARIANTS ( 12 Selected Examples):

.0001 OSTEOGENESIS IMPERFECTA, TYPE XI
FKBP10, 33-BP DEL, NT321
In all affected members of 5 consanguineous Turkish families with OI type XI (OI11; 610698), Alanay et al. (2010) identified homozygosity for an in-frame deletion in FKBP10 (321_353del), predicted to result in deletion of 11 amino acids (met107_leu117del). RT-PCR products derived from fibroblasts of 1 affected individual showed that this mutation leads to synthesis of FKBP65 mRNA containing the deletion.

.0002 OSTEOGENESIS IMPERFECTA, TYPE XI
BRUCK SYNDROME 1, INCLUDED
FKBP10, 1-BP DUP, 831C
In 3 Mexican sibs with OI type XI (OI11; 610968), the offspring of consanguineous parents, Alanay et al. (2010) identified homozygosity for a 1-bp duplication in the FKBP10 gene (831dupC), producing a translational frameshift (Gly278ArgfsTer95) predicted to result in a stop codon 94 amino acids downstream. RT-PCR performed on mRNA obtained from skin fibroblasts showed absence of FKBP65 cDNA, demonstrating that the mutation leads to a functional null allele.

In 2 sibs with a moderately severe form of OI, one with and one without congenital joint contractures (BRKS1; 259450), and in another patient with OI and joint contractures, Kelley et al. (2011) identified homozygosity for the same 1-bp duplication in the FKBP gene. The parents were consanguineous in each case. In 2 other patients with OI and congenital joint contractures, Kelley et al. (2011) identified this mutation in compound heterozygous state with different mutations in the FKBP gene; see 607063.0005 and 607063.0006.

Shaheen et al. (2011) identified homozygosity for the 831dupC mutation in a Saudi patient with fixed flexion contractures, mainly at the hips, knees, and elbows with bilateral talipes deformity. Femur fracture diagnosed at 3 weeks of age. The patient's parents were first cousins.

.0003 BRUCK SYNDROME 1
FKBP10, 8-BP DUP, NT1016
In 2 brothers with Bruck syndrome (BRKS1; 259450), Shaheen et al. (2010) identified a homozygous 8-bp insertion (1016_1023dup) resulting in a frameshift and premature termination of the protein (Thr342GlyfsX26). This mutation predicts complete loss of the fourth PPI domain of FKBP65. Shaheen et al. (2010) suggested that the brothers had a form of Bruck syndrome. The authors noted that the brothers also had a previously reported sequence variant (P205A) in COL1A1 (120150) of unknown pathogenicity.

.0004 OSTEOGENESIS IMPERFECTA, TYPE XI
FKBP10, 35-BP DEL, NT122
In a patient with a moderately severe form of OI (OI11; 610968), the daughter of consanguineous unaffected Indian Punjabi parents, Kelley et al. (2011) identified a 35-kb deletion (122_156del) in the FKBP10 gene, resulting in a frameshift and premature stop codon (Leu41GlnfsTer22).

.0005 BRUCK SYNDROME 1
FKBP10, 1-BP DUP, 1276G
In a patient with Bruck syndrome (BRKS1; 259450), the daughter of nonconsanguineous South African parents, Kelley et al. (2011) identified compound heterozygosity for mutations in the FKBP10 gene: a 1-bp deletion (607063.0002) and a 1-bp duplication (1276dupG) resulting in a frameshift and premature stop codon (Glu426ArgfsTer54).

.0006 BRUCK SYNDROME 1
FKBP10, ARG115GLN
In a patient with Bruck syndrome (BRKS1; 259450), the daughter of nonconsanguineous Caucasian parents, Kelley et al. (2011) identified compound heterozygosity for mutations in the FKBP10 gene: a 1-bp deletion (607063.0002) and a 344G-A transition resulting in an arg115-to-gln (R115Q) substitution.

In affected members of a family with Bruck syndrome reported by Breslau-Siderius et al. (1998) and Bank et al. (1999), Schwarze et al. (2013) identified homozygosity for the R115Q mutation.

.0007 BRUCK SYNDROME 1
FKBP10, 1-BP DUP, 743C
Shaheen et al. (2011) described a consanguineous Saudi family in which 3 sisters and 2 male cousins had Bruck syndrome (BRKS1; 259450) and the same novel mutation in the FKBP10 gene, a 1-bp duplication (743dupC) resulting in a frameshift and premature termination (Gln249ThrfsTer12). Four of those affected did not have contractures; the fifth had abnormal skin folds at the popliteal area that caused flexion contractures of the knees, which were noticed at birth, and he later had frequent fractures.

.0008 OSTEOGENESIS IMPERFECTA, TYPE XI
FKBP10, ARG403TER
In 3 male German sibs with a severe form of OI (OIXI; 610968) and dentinogenesis imperfecta, Steinlein et al. (2011) identified a homozygous 1207C-T transition in exon 7 of the FKBP10 gene, resulting in an arg403-to-ter (R403X) substitution. None of the brothers showed contractures or webbing.

.0009 BRUCK SYNDROME 1
OSTEOGENESIS IMPERFECTA, TYPE XI, INCLUDED
FKBP10, 2-BP DEL/1-BP INS, NT1271
In probands from 2 unrelated consanguineous Egyptian families segregating Bruck syndrome (BRKS1; 259450), Puig-Hervas et al. (2012) identified a homozygous indel mutation in exon 8 of the FKBP10 gene (1271_1272delCCinsA), resulting in a frameshift (Ala424AspfsTer12).

In a Palestinian pedigree segregating moderate and lethal forms of OI, Barnes et al. (2012) identified this homozygous indel mutation in a proband from one branch of the family with OI type XI (OI11; 610968), and a homozygous deletion in the PPIB gene (123841.0004) in a proband from another branch of the family with OI type IX (259440).

.0010 BRUCK SYNDROME 1
FKBP10, GLU113LYS
In affected members of a family with Bruck syndrome (BRKS1; 259450), originally described by McPherson and Clemens (1997), Schwarze et al. (2013) identified homozygosity for a 337G-A transition in the FKBP10 gene, resulting in a glu113-to-lys (E113K) substitution.

.0011 OSTEOGENESIS IMPERFECTA, TYPE XI
FKBP10, 1-BP DUP, 948T
In 17 patients with osteogenesis imperfecta (OI11; 610968) from 10 families originating from Samoa or nearby islands in the South Pacific, Schwarze et al. (2013) identified a founder mutation in the FKBP10 gene, a 1-bp duplication (948dupT) resulting in a frameshift (Ile317TyrfsTer56) and mRNA instability. The mutation occurred in homozygosity in 9 families; in 1 family, the 948dupT mutation was inherited from a Samoan mother and an 831dupC mutation (607063.0002) from a European father.

.0012 BRUCK SYNDROME 1
FKBP10, 3-BP DEL, 877TAC
In affected members of multiple pedigrees with Kuskokwim disease (BRKS1; 259450), Barnes et al. (2013) identified a homozygous 3-bp deletion in exon 5 of the FKBP10 gene (c.877_879delTAC, NM_021939.3) resulting in the deletion of a highly conserved tyrosine residue (Tyr293del) in the third peptidyl-prolyl cis-trans isomerase domain. Three percent (3/96 alleles) of controls in the Kuskokwim region were shown to be carriers of the Tyr293 variant.

Tags: 17q21.2