Search

Background: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. OI patients of autosomal recessive inheritance are extremely rare, of which OI type XIII is attributable to mutation in BMP1 gene., Case Report: Here, we detect the pathogenic mutations and analyze their relation to the phenotypes in a Chinese family with OI using next-generation sequencing (NGS) and Sanger sequencing. We also evaluate the efficacy of alendronate treatment in the patient with OI type XIII. The clinical phenotypes of the patient included recurrent fractures, muscle weakness, bone deformity, macrocephaly and elbow contractures, but no blue sclera or dentinogenesis imperfecta. High-resolution peripheral quantitative computed tomography revealed high bone mineral density and bone volume, but reduced trabecular numbers, increased porosity and comprised strength in this patient. Novel heterozygous mutations of c.1324G > T (p.Asp442Tyr) and c.148 + 1G > A in BMP1 gene were found in the proband, which would affect the CUB2 domain and the prodomain of mutant proteins. The parents were heterozygous carriers for the two mutations respectively, but with normal phenotype., Conclusions: We report for the first time that the novel pathogenic mutations in BMP1 can lead to the extremely rare OI type XIII, which exhibit unique characters of high bone mass, but with impaired bone microstructure and comprised bone strength. Alendronate is beneficial in increasing bone mineral density and decreasing bone resorption biomarkers, but concerns still remain whether it can reduce fracture incidence in this rare type of OI., (Copyright © 2018. Published by Elsevier B.V.)

Backgrounds: SERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis., Objective: To assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis., Methods: Known candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1, CLO1A2, IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls., Results: Serum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66±1.60μg/ml) than in OI patients with other pathogenic mutations (4.88±1.43-7.07±2.43μg/ml), carriers of one copy of SERPINF1 mutation (4.94±2.35μg/ml), and normal controls (7.29±2.31μg/m) (P<0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r=0.310, P=0.004), BMI (r=0.253, P=0.020) and alanine aminotransferase (r=0.291, P=0.007)., Conclusions: Extremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. OI cases of autosomal recessive inheritance are rare, and OI type XI is attributable to mutation of the FKBP10 gene. Here, we used next-generation sequencing and Sanger sequencing to detect mutations in FKBP10 and to analyze their relation to the phenotypes of OI type XI in three Chinese patients. We also evaluated the efficacy of zoledronic acid treatment in these patients. Two of the affected patients had novel compound heterozygous mutations, one patient with c.343C>T (p.R115X) in exon 2 and c.1085delC (p.A362fsX1) in exon 7, and the other patient with c.879C>G (p.Y293X) in exon 5 and c.918-3C>G in intron 5. In the third proband, we identified a homozygous single base-pair duplication, c.831dupC (p.G278RfsX95) in exon 5. In conclusion, we report for the first time that these novel pathogenic mutations of FKBP10 can lead to the extremely rare type XI OI without contractures, which expands the genotypic spectrum of OI. The phenotypes of these patients are similar to patients with types III or IV OI, and zoledronic acid is effective in increasing BMD, inhibiting bone resorption biomarkers and reducing fractures of these patients.

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271&#95;279dup, p.Ala91&#95;Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498&#95;499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202&#95;1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271&#95;279dup, p.Ala91&#95;Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.

Objective: Osteogenesis imperfecta (OI) is characterized by low bone mass and recurrent fractures. Adults with OI are often treated with oral or intravenous bisphosphonates (BPs). We investigated the clinical phenotypes of adult OI patients and prospectively compared the efficacy of oral alendronate (ALN) with intravenous zoledronic acid (ZOL) in OI patients., Methods: This 24-month, observational, randomized clinical study included 60 adult patients with OI. We compared the differences in bone mineral density (BMD) and bone turnover biomarkers between OI adults and healthy subjects. Thereafter, OI patients were randomized at a 2:1 ratio to receive either weekly oral ALN 70 mg or once-yearly infusion of ZOL 5 mg. The efficacy outcomes were changes in BMD, bone turnover biomarkers, and fracture incidence., Results: Adult OI patients had significantly lower BMD and significantly higher cross-linked C-telopeptide of type I collagen (β-CTX) levels than age-/sex-/BMI-matched healthy subjects. A total of 52 patients completed the 24-month clinical study. BMD at lumbar spine, femoral neck, and total hip were equivalently elevated in the ALN (10.5, 13.2, and 14.7%, respectively) and ZOL (11.3, 13.7, and 11.7%, respectively; all P>.05) groups. Serum alkaline phosphatase decreased by 30.3% in the ALN group and 37.3% in the ZOL group (P = .12), and β-CTX decreased by 58.0% in the ALN group and 63.6% in the ZOL group (P = .48). Compared to the prior fracture rates, clinical fracture incidences were decreased in the ALN and ZOL groups (both P<.05)., Conclusion: Adults with OI present significantly lower bone mass and higher bone resorption biomarkers than healthy populations. Oral ALN and intravenous ZOL are equally effective at increasing BMD and inhibiting bone turnover in adults with OI. The treatment may reduce fractures in this study, but further efforts are still needed to demonstrate the anti-fracture efficacy of BPs., Abbreviations: 25OHD = 25-hydroxyvitamin D ALN = alendronate ALP = alkaline phosphatase BMD = bone mineral density BMI = body mass index BP = bisphosphonate β-CTX = cross-linked C-telopeptide of type I collagen FN = femoral neck LS = lumbar spine OI = osteogenesis imperfecta RCT = randomized controlled trial TH = total hip ZOL = zoledronic acid.

Background: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. Most OI cases follow an autosomal dominant pattern of inheritance and are attributed to mutations in genes encoding type I collagen (COL1A1/COL1A2). Genomic structural variations involving type I collagen genes are extremely rare in OI., Case Report: In this study, we characterized a de novo balanced translocation of t(5;7)(q32;q21.3) that caused an extremely rare type of OI in a patient from a non-consanguineous family. The clinical phenotypes of this OI included recurrent fractures, low bone mass, macrocephaly, blue sclera and failure to thrive. Next-generation sequencing was used to identify the translocation, and Sanger sequencing was used to validate and map the breakpoints. The breakpoint on chromosome 7 disrupted the COL1A2 gene in the 17th exon, presumed to affect type I collagen production and give rise to OI. The breakpoint on chromosome 5 disrupted the protein phosphatase 2 regulatory subunit B, beta gene (PPP2R2B) within the first intron., Conclusions: This is the first report of a copy-neutral structural variant involving COL1A2 that leads to a rare type of OI. This study expands the genotypic spectrum of OI and demonstrates the effectiveness of targeted sequencing for breakpoint mapping., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Osteogenesis imperfecta (OI) is a group of clinically and genetically heterogeneous disorders characterized by decreased bone mass and recurrent bone fractures. Transmembrane protein 38B (TMEM38B) gene encodes trimeric intracellular cation channel type B (TRIC-B), mutations of which will lead to the rare form of autosomal recessive OI. Here we detected pathogenic gene mutations in TMEM38B and investigated its phenotypes in three children with OI from two non-consanguineous families of Chinese Han origin. The patients suffered from recurrent fractures, low bone mass, mild bone deformities and growth retardation, but did not have impaired hearing or dentinogenesis imperfecta. Next-generation sequencing and Sanger sequencing revealed a homozygous novel acceptor splice site variant (c.455-7T>G in intron 3, p.R151&#95;G152insVL) in family 1 and a homozygous novel nonsense variant (c.507G>A in exon 4, p.W169X) in family 2. The parents of the probands were all heterozygous carriers of these mutations. We reported the phenotype and novel mutations in TMEM38B of OI for the first time in Chinese population. Our findings of the novel mutations in TMEM38B expand the pathogenic spectrum of OI and strengthen the role of TRIC-B in the pathogenesis of OI.

Backgrounds SERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis. Objective To assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis. Methods Known candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1 , CLO1A2 , IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls. Results Serum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66 ± 1.60 μg/ml) than in OI patients with other pathogenic mutations (4.88 ± 1.43–7.07 ± 2.43 μg/ml), carriers of one copy of SERPINF1 mutation (4.94 ± 2.35 μg/ml), and normal controls (7.29 ± 2.31 μg/m) ( P < 0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r = 0.310, P = 0.004), BMI (r = 0.253, P = 0.020) and alanine aminotransferase (r = 0.291, P = 0.007). Conclusions Extremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment. [ABSTRACT FROM AUTHOR]