What is new in genetics and osteogenesis imperfecta classification?

Valadares, Eugênia Ribeiro; Carneiro, Túlio B.; Santos, Paula M.; Oliveira, Ana Cristina; Zabel, Bernhard

doi:10.1016/j.jped.2014.05.003

Cited by 91 publications

(73 citation statements)

References 33 publications

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“…Many mutations in the COL1A2 gene are known to cause autosomal dominant osteogenesis imperfecta (OI), a generalized connective tissue disorder characterized mainly by bone fragility from early childhood and low BMD . Other characteristics are short stature, blue sclerae, dentinogenesis imperfecta, hearing deficit, fragile skin, and sometimes joint hyperlaxity . Osteogenesis imperfecta presents with variable degree of severity.…”

Section: Resultsmentioning

confidence: 99%

Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland

Styrkársdóttir

Þorleifsson

Eiríksdottir

et al. 2015

Journal of Bone and Mineral Research

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We conducted a genome-wide association study of low bone mineral density (BMD) at the hip and spine utilizing sequence variants found through whole-genome sequencing of 2636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause the autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low BMD and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (p ¼ 1.8 Â 10 À7 , odds ratio [OR] ¼ 4.61 [95% confidence interval (CI) 2.59, 8.18]), whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (p ¼ 1.9 Â 10 À8 , OR ¼ 9.34 [95% CI 4.28, 20.3]). Association with fractures was p ¼ 2.2 Â 10 À5 , OR ¼ 3.75 (95% CI 2.03, 6.93) and p ¼ 0.0023, OR ¼ 4.32 (95% CI 1.69, 11.1), respectively. The carriers of these variants do not have signs of osteogenesis imperfecta other than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way.

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Section: Resultsmentioning

confidence: 99%

Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland

Styrkársdóttir

Þorleifsson

Eiríksdottir

et al. 2015

Journal of Bone and Mineral Research

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“…A collection of studies has demonstrated that PLOD2 is essential for the biogenesis of normal mature collagen and the stability of collagen cross-links [6, 7]. Due to the crucial role of collagen in formation of extracellular matrix, PLOD2 has been implicated in various pathological processes, including systemic sclerosis [8], osteogenesis imperfecta [9] and join contractures [10]. Importantly, deregulation of PLOD2 has been observed in several kinds of cancers [11–13].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma

et al. 2017

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Gliomas are the most common form of malignant primary brain tumors with poor 5-year survival rate. Dysregulation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was observed in gliomas, but the specific role and molecular mechanism of PLOD2 in glioma have not been reported yet. In this study, PLOD2 was found to be frequently up-regulated in glioma and could serve as an independent prognostic marker to identify patients with poor clinical outcome. Knockdown of PLOD2 inhibited proliferation, migration and invasion of glioma cells in vitro and in vivo. Mechanistically, inhibition of PLOD2 inactivated PI3K/AKT signaling pathway and thus regulated the expression of its downstream epithelial–mesenchymal transition (EMT)-associated regulators, including E-cadherin, vimentin, N-cadherin, β-catenin, snail and slug in glioma cells. Moreover, PLOD2 could be induced by hypoxia-inducible factor-1α (HIF-1α) via hypoxia, thereby promoting hypoxia-induced EMT in glioma cells. Our data suggests that PLOD2 may be a potential therapeutic target for patients with glioma.

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“…[8] Although OI-3 is rare, studies in affected persons from different parts of the world have revealed causative mutations in several genes: CRTAP, P3H1, FKBP10, PPIB, SERPINH1, SERPINF1, BMP1, SP7, WNT1, TMEM38B, PLOD2 and CREB3L1. [9] Mutations in FKBP10, which encodes FKBP65, have been reported in affected persons of Turkish, Mexican-American, [10] German, [11] Saudi Arabian, [12] indigenous black South African, [13] Indonesian, [14] Egyptian, [15] Italian, [16] Palestinian, [17] Lebanese, Sudanese, [18] Samoan, North Ameri can [17,19] and Chinese ancestry. [20] In this context, homozygosity for a specific nucleotide insertion, NM_021939.3:c.831dupC, in the FKBP10 gene has been demonstrated in OI-3 patient populations indigenous to Europe, [10][11][12][13] Asia, [21] Africa [13,18] and the Middle East.…”

Section: Researchmentioning

confidence: 99%

Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10

et al. 2017

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Corresponding author: A Vorster (vorster@sun.ac.za)Background. A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment. Objective. To delineate the molecular basis for the condition. Methods. Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population. Results. Following polymerase chain reaction amplification and direct cycle sequencing, FKBP10 mutations were identified in 45.1% (41/91) OI-3-affected persons. The homozygous FKBP10 c.831dupC frameshift mutation was confirmed in 35 affected individuals in the study cohort. Haplotype analysis suggests that this mutation is identical among these OI-3-affected persons by descent, thereby confirming that they had a common ancestor. Compound heterozygosity of this founder mutation was observed, in combination with three different deleterious FKBP10 mutations, in six additional persons in the cohort. Four of these individuals had the c.831delC mutation. Conclusion. The burden of the disorder, both in frequency and severity, warrants the establishment of a dedicated service for molecular diagnostic confirmation and genetic management of persons and families with OI in southern Africa.

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What is new in genetics and osteogenesis imperfecta classification?

Cited by 91 publications

References 33 publications

Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland

Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland

Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma

Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10

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