Novel Mutations in FKBP10 and PLOD2 Cause Rare Bruck Syndrome in Chinese Patients

Zhou, Peiran; Liu, Yi; Lv, Fang; Nie, Min; Jiang, Yan; Wang, Ou; Xia, Weibo; Xing, Xiaoping; Li, Mei

doi:10.1371/journal.pone.0107594

Cited by 34 publications

(44 citation statements)

References 32 publications

(37 reference statements)

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“…Defects in FKBP65 result in a range of overlapping phenotypes, including moderate to severe osteogenesis imperfecta, Bruck syndrome (characterized by severe osteogenesis imperfecta with congenital contractures) and Kuskokwim syndrome (congenital contractures with minimal skeletal involvement) 15,61,[71][72][73][74][75][76][77][78] . Remarkable phenotypic variability is observed, even within families.…”

Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

545

582

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

545

582

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“…In addition, mutations in FKBP10 result in BS type 1 (MIM 259450) (27,(29)(30)(31)(32)(33)(34) and in osteogenesis imperfecta and Kuskokwin syndrome (35-38). As is the case for PLOD2 mutations, FKBP10 mutations result in a dramatic underhydroxylation of collagen telopeptide Lys and a subsequent decrease in the pyridinoline crosslinking of collagen type I in bone (26,32,39).…”

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confidence: 99%

“…Mutations in PLOD2 are linked to the development of Bruck syndrome type 2 (BS2) (MIM 609220) (25)(26)(27)(28), a heritable autosomal recessive bone disease characterized by congenital contractures with pterygia, early onset of bone fractures, postnatal short stature, and severe limb deformity and progressive scoliosis. In addition, mutations in FKBP10 result in BS type 1 (MIM 259450) (27,(29)(30)(31)(32)(33)(34) and in osteogenesis imperfecta and Kuskokwin syndrome (35)(36)(37)(38).…”

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confidence: 99%

Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2

Gjaltema

Stoel

Boersema

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Collagens are subjected to extensive posttranslational modifications, such as lysine hydroxylation. Bruck syndrome (BS) is a connective tissue disorder characterized at the molecular level by a loss of telopeptide lysine hydroxylation, resulting in reduced collagen pyridinoline cross-linking. BS results from mutations in the genes coding for lysyl hydroxylase (LH) 2 or peptidyl-prolyl cis-trans isomerase (PPIase) FKBP65. Given that the immunophilin FKBP65 does not exhibit LH activity, it is likely that LH2 activity is somehow dependent on FKPB65. In this report, we provide insights regarding the interplay between LH2 and FKBP65. We found that FKBP65 forms complexes with LH2 splice variants LH2A and LH2B but not with LH1 and LH3. Ablating the catalytic activity of FKBP65 or LH2 did not affect complex formation. Both depletion of FKBP65 and inhibition of FKBP65 PPIase activity reduced the dimeric (active) form of LH2 but did not affect the binding of monomeric (inactive) LH2 to procollagen Iα1. Furthermore, we show that LH2A and LH2B cannot form heterodimers with each other but are able to form heterodimers with LH1 and LH3. Collectively, our results indicate that FKBP65 is linked to pyridinoline cross-linking by specifically mediating the dimerization of LH2. Moreover, FKBP65 does not interact with LH1 and LH3, explaining why in BS triple-helical hydroxylysines are not affected. Our results provide a mechanistic link between FKBP65 and the loss of pyridinolines and may hold the key to future treatments for diseases related to collagen cross-linking anomalies, such as fibrosis and cancer.collagen cross-linking | lysyl hydroxylase | FKBP65 | Bruck syndrome | fibrosis C ollagen I is an essential component of the extracellular matrix (ECM) of tissues such as bone and skin, and is involved in a wide variety of biological processes. A deregulated synthesis of collagen type I results in pathologies ranging from severe bone and skin anomalies to fibrosis (1-5). Hydroxylation of specific lysine (Lys) residues into 5-hydroxylysine (Hyl) is performed by lysyl hydroxylases (LHs), also known as the procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family. Collagens deposited in the ECM are stabilized by the formation of intermolecular crosslinks by members of the lysyl oxidase family, LOX and LOXL (6). Two collagen cross-linking pathways have been identified, the allysine route and the hydroxyallysine route (7). In the allysine route, a telopeptide Lys is oxidized by lysyl oxidases into an aldehyde; in the hydroxyallysine route, this occurs with a telopeptide Hyl. In turn, the reactive aldehydes interact with the Lys or Hyl residues in the helical part of collagen to form difunctional and finally trifunctional cross-links (8-10). The trifunctional cross-links derived from the hydroxyallysine route are referred to as pyridinolines. Collagens cross-linked by means of pyridinolines are difficult to degrade (11-13).The LH family consists of three individual members, designated LH1, LH2, and LH3. Hydroxylation of Lys present...

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“…They are phenotypically indistinguishable but caused by mutations in two distinct genes, i.e. FKBP 10 and PLOD 2 (encoding LH2), respectively101718. The former gene encodes FK506 binding protein 65 (FKBP65, hereafter), an endoplasmic reticulum-resident peptidyl prolyl cis-trans isomerase (PPIase) and chaperone molecule.…”

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FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch

Chen

Terajima

Banerjee

et al. 2017

Sci Rep

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Bruck Syndrome is a connective tissue disease associated with inactivating mutations in lysyl hydroxylase 2 (LH2/PLOD2) or FK506 binding protein 65 (FKBP65/FKBP10). However, the functional relationship between LH2 and FKBP65 remains unclear. Here, we postulated that peptidyl prolyl isomerase (PPIase) activity of FKBP65 positively modulates LH2 enzymatic activity and is critical for the formation of hydroxylysine-aldehyde derived intermolecular collagen cross-links (HLCCs). To test this hypothesis, we analyzed collagen cross-links in Fkbp10-null and –wild-type murine embryonic fibroblasts. Although LH2 protein levels did not change, FKBP65 deficiency significantly diminished HLCCs and increased the non-hydroxylated lysine-aldehyde–derived collagen cross-links (LCCs), a pattern consistent with loss of LH2 enzymatic activity. The HLCC-to-LCC ratio was rescued in FKBP65-deficient murine embryonic fibroblasts by reconstitution with wild-type but not mutant FKBP65 that lacks intact PPIase domains. Findings from co-immunoprecipitation, protein-fragment complementation, and co-immunofluorescence assays showed that LH2 and FKBP65 are part of a common protein complex. We conclude that FKBP65 regulates LH2-mediated collagen cross-linking. Because LH2 promotes fibrosis and cancer metastasis, our findings suggest that pharmacologic strategies to target FKBP65 and LH2 may have complementary therapeutic activities.

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Novel Mutations in FKBP10 and PLOD2 Cause Rare Bruck Syndrome in Chinese Patients

Cited by 34 publications

References 32 publications

Osteogenesis imperfecta

Osteogenesis imperfecta

Disentangling mechanisms involved in collagen pyridinoline cross-linking: The immunophilin FKBP65 is critical for dimerization of lysyl hydroxylase 2

FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch

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