Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta

Alanay, Yasemin; Avaygan, Hrispima; Camacho, Natalia; Ütine, Gülen Eda; Boduroğlu, Koray; Aktaş, Dilek; Alikaşifoğlu, Mehmet; Tunçbılek, Ergül; Orhan, Dıclehan; Bakar, Filiz; Zabel, Bernard; Superti‐Furga, Andrea; Bruckner‐Tuderman, Leena; Curry, Cindy J.R.; Pyott, Shawna M.; Byers, Peter H.; Eyre, David R.; Baldridge, Dustin; Lee, Brendan; Merrill, Amy E.; Davis, Elaine C.; Cohn, Daniel H.; Akarsu, Nurten; Krakow, Deborah

doi:10.1016/j.ajhg.2010.09.002

Cited by 83 publications

(138 citation statements)

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“…Accumulation of aggregated procollagen in the ER of FKBP65-deficient cells [12] indicates that FKBP65 is important for procollagen folding or trafficking. In vitro studies suggest that FKBP65 may stabilize the triple helix like HSP47 (Figure 3) and catalyze proline peptide bond isomerization [44], thus accelerating procollagen folding.…”

Section: Chaperoning Dilemma: Encouraging Success Vs Discouraging Famentioning

confidence: 99%

“…In vitro studies suggest that FKBP65 may stabilize the triple helix like HSP47 (Figure 3) and catalyze proline peptide bond isomerization [44], thus accelerating procollagen folding. However, no overhydroxylation or overglycosylation of lysines -- expected to accompany slower procollagen folding [45] -- has been detected in FKBP65-deficient cells [12]. Recent reports of OI with joint contractures (Bruck syndrome) in several patients with FKBP65 deficiencies [15, 16] might resolve this discrepancy.…”

Section: Chaperoning Dilemma: Encouraging Success Vs Discouraging Famentioning

confidence: 99%

“…Procollagen mutations and chaperone deficiencies result in accumulation of partially unfolded or misfolded procollagen in the ER of these cells [12, 22, 23, 56, 57]. The resulting change in the ER state, which we refer to as ER stress, may affect cell function and thus contribute to osteogenesis pathology.…”

Section: Chaperoning Dilemma: Encouraging Success Vs Discouraging Famentioning

confidence: 99%

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Chaperoning osteogenesis: new protein-folding disease paradigms

Makareeva

Aviles

Leikin

2011

Trends in Cell Biology

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Recent discoveries of severe bone disorders in patients with deficiencies in several endoplasmic reticulum chaperones are reshaping the discussion of type I collagen folding and related diseases. Type I collagen is the most abundant protein in all vertebrates and a crucial structural molecule for bone and other connective tissues. Its misfolding causes bone fragility, skeletal deformities and other tissue failures. Studies of newly discovered bone disorders indicate that collagen folding, chaperones involved in the folding process, cellular responses to misfolding, and related bone pathologies may not follow conventional protein folding paradigms. In this review, we examine the features that distinguish collagen folding from that of other proteins and describe findings that are beginning to reveal how cells manage collagen folding and misfolding. We discuss implications of these studies on general protein folding paradigms, unfolded protein response in cells and protein folding diseases. Sans chaperones: osteogenesis choreography gone astrayBone consists of flexible type I collagen fibers and hard hydroxyappatite mineral, making bone material strong yet not brittle. Bone formation (osteogenesis) involves an intricate choreography of specialized cells (Figure 1). Osteoblasts deposit collagen fibers and promote mineralization, osteoclasts resorb older bone and osteocytes act as mechano-sensors that are embedded in bone. These cells interact with each other and are regulated by outside signals from cytokines, hormones and the sympathetic nervous system [1][2][3]. Osteogenesis disorders may be caused by bone cell malfunctions and defects in the collagen matrix.Endoplasmic reticulum (ER) chaperones were brought to the forefront of osteogenesis research by recent discoveries of several new forms of osteogenesis imperfecta (OI). OI is a group of hereditary disorders characterized by bone fractures and deformities [4,5]. Deficiencies in five ER chaperones --CRTAP, P3H1, CYPB, FKBP65, and HSP47 --were found to cause severe OI by leading astray type I collagen folding and osteogenesis choreography [6][7][8][9][10][11][12][13][14][15][16]. The apparent roles of these chaperones in disease pathology, however, presented an unexpected puzzle.Most chaperones assist protein folding by protecting unfolded chains from nonspecific interactions and by catalyzing peptide and disulfide bond isomerization [17][18][19]. However, the functions of CRTAP, P3H1, CYPB, FKBP65, and HSP47 in collagen folding do not Corresponding author: Leikin, S. (leikins@mail.nih.gov).

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Section: Chaperoning Dilemma: Encouraging Success Vs Discouraging Famentioning

confidence: 99%

Section: Chaperoning Dilemma: Encouraging Success Vs Discouraging Famentioning

confidence: 99%

Section: Chaperoning Dilemma: Encouraging Success Vs Discouraging Famentioning

confidence: 99%

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Chaperoning osteogenesis: new protein-folding disease paradigms

Makareeva

Aviles

Leikin

2011

Trends in Cell Biology

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“…In the other four individuals with OI type IV, exome sequencing revealed that one patient was compound heterozygous for a deletion of the entire exon 1 and a stopgain mutation in FKBP10 (data not shown), a gene associated with recessive OI 12. No conclusive result emerged from the analysis in the other three patients (table 1).…”

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confidence: 91%

Mutations in WNT1 are a cause of osteogenesis imperfecta

et al. 2013

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“…Known defects include biallelic mutations in LEPRE1 [3-5], CRTAP [5,6], PPIB [7,8], BMP1 [9,10], and PLOD2 [11]. Mutations in chaperones (including Hsp47 ( SERPINH1 ) and FKBP10) impair intracellular collagen trafficking with intracellular retention or aggregation of collagen molecules and show dilation of the ER on electron microscopy, resulting in OI or related phenotypes [12-14]. Finally, rare other defects linked to distinct mechanisms involve the transcription factor osterix ( SP7 ) [15], pigment epithelium derived factor ( SERPINF1 ) [16] and transmembrane protein 38B ( TMEM38B ) [17,18].…”

Section: Introductionmentioning

confidence: 99%

Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans

Symoens

Malfait

D’hondt

et al. 2013

Orphanet J Rare Dis

114

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Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous brittle bone disorder. Whereas dominant OI is mostly due to heterozygous mutations in either COL1A1 or COL1A2, encoding type I procollagen, recessive OI is caused by biallelic mutations in genes encoding proteins involved in type I procollagen processing or chaperoning. Hitherto, some OI cases remain molecularly unexplained. We detected a homozygous genomic deletion of CREB3L1 in a family with severe OI. CREB3L1 encodes OASIS, an endoplasmic reticulum-stress transducer that regulates type I procollagen expression during murine bone formation. This is the first report linking CREB3L1 to human recessive OI, thereby expanding the OI gene spectrum.

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Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta

Cited by 83 publications

References 1 publication

Chaperoning osteogenesis: new protein-folding disease paradigms

Chaperoning osteogenesis: new protein-folding disease paradigms

Mutations in WNT1 are a cause of osteogenesis imperfecta

Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans

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