Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.
ABSTRACT Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.
SourceAvailable from: Walter L Eckalbar[Show abstract] [Hide abstract]
ABSTRACT: The autism susceptibility candidate 2 gene (AUTS2) has been associated with multiple neurological diseases including autism spectrum disorders (ASDs). Previous studies showed that AUTS2 has an important neurodevelopmental function and is a suspected master regulator of genes implicated in ASD-related pathways. However, the regulatory role and targets of Auts2 are not well known. Here, by using ChIP-seq (chromatin immunoprecipitation followed by deep sequencing) and RNA-seq on mouse embryonic day 16.5 forebrains, we elucidated the gene regulatory networks of Auts2. We find that the majority of promoters bound by Auts2 belong to genes highly expressed in the developing forebrain, suggesting that Auts2 is involved in transcriptional activation. Auts2 non-promoter-bound regions significantly overlap developing brain-associated enhancer marks and are located near genes involved in neurodevelopment. Auts2-marked sequences are enriched for binding site motifs of neurodevelopmental transcription factors, including Pitx3 and TCF3. In addition, we characterized two functional brain enhancers marked by Auts2 near NRXN1 and ATP2B2, both ASD-implicated genes. Our results implicate Auts2 as an active regulator of important neurodevelopmental genes and pathways and identify novel genomic regions that could be associated with ASD and other neurodevelopmental diseases.Translational Psychiatry 09/2014; 4(9):e431. DOI:10.1038/tp.2014.78 · 4.36 Impact Factor
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ABSTRACT: Bruck syndrome (BS) is an extremely rare form of osteogenesis imperfecta characterized by congenital joint contracture, multiple fractures and short stature. We described the phenotypes of BS in two Chinese patients for the first time. The novel compound heterozygous mutations c.764_772dupACGTCCTCC (p.255_257dupHisValLeu) in exon 5 and c.1405G>T (p.Gly469X) in exon 9 of FKBP10 were identified in one proband. The novel compound heterozygous mutations c.1624delT (p.Tyr542Thrfs*18) in exon 14 and c.1880T>C (p.Val627Ala) in exon 17 of PLOD2 were identified in another probrand. Intravenous zoledronate was a potent agent for these patients, confirmed the efficacy of bisphosphonates on this disease. In conclusion, the novel causative mutations identified in the patients expand the genotypic spectrum of BS.PLoS ONE 09/2014; 9(9):e107594. DOI:10.1371/journal.pone.0107594 · 3.53 Impact Factor
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ABSTRACT: Bone is a composite material that resembles reinforced concrete. The collagen matrix plays the role of reinforcement, whereas hydroxyapatite crystals are cementing material. Collagen fibers are responsible for the tensile strength of bones and prevent fractures from extending; the mineral phase is able to withstand compaction loads. A right balance of these two parts synergistically provides the required stiffness for bone. Collagen abnormalities, such as reduced amount, disturbed composition, defects in structure and/or supramolecular organization as well as insufficient or defective mineralization, lead to osteogenesis imperfecta (OI), also known as brittle bone disease. Until recently, mutations in the type I collagen genes COL1A1 and COL1A2 were the only known causes of the disease, which cover about 90 % of diagnosed OI. Within the last decade, we have witnessed a burst in the identification of new OI mutations in other genes. Here we summarize our knowledge of these mutations and their impact on bone quality.12/2013; 1(4):239-246. DOI:10.1007/s40142-013-0026-2