Allele dependent silencing of collagen type I using small interfering RNAs targeting 3[prime]UTR indels [ndash] a novel therapeutic approach in osteogenesis imperfecta

Over 85% of osteogenesis imperfecta (OI) cases associates to mutations in procollagen type I genes (COL1A1 or COL1A2), however, no hot spots were linked to particular clinical phenotypes. The 8 patients whom were clinically diagnosed with OI are from Polish population with no ethnic background indicated. Six unpublished mutations were detected in eight patients diagnosed with OI. Genotypes for polymorphisms (Sp1 - rs1800012 and PvuII - rs412777), linked to bone formation and metabolism were also determined. In COL1A1 gene the mutations were found in exons 2, 22, 50 and in introns 13 and 51. In COL1A2 one mutation was identified in exon 22. Mutations of deletion type in COL1A1 that resulted in OI type I an effect neither on collagen type I secretion nor its intracellular accumulation were detected. Also, a single base substitution in I13 (c.904-9 G>T) was associated with OI type I. The OI type III was associated with single base change in I51 of COL1A1, possibly causing an exon skipping. Also, a missense mutation in COL1A2 changing Gly®Cys in the central part of triple helical domain of the collagen type I molecule caused OI type III. It affected secretion of heterotrimeric form of procollagen type I. However, no intracellular accumulation of procollagen chains could be detected. Mutation in COL1A2 affected its incorporation to procollagen type I. The results shall help in genetic counseling of OI patients and provide rational support in making by them and their families conscious, life important decisions.

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Alendronate for the Treatment of Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-0636 ◽

2011 ◽

Vol 96 (2) ◽

pp. 355-364 ◽

Cited By ~ 132

Author(s):

L. M. Ward ◽

F. Rauch ◽

M. P. Whyte ◽

J. D'Astous ◽

P. E. Gates ◽

...

Keyword(s):

Physical Activity ◽

Osteogenesis Imperfecta ◽

Bone Pain ◽

Collagen Type ◽

Collagen Type I ◽

Fracture Incidence ◽

Controlled Study ◽

Type I ◽

Z Score ◽

Cortical Width

abstract Context: Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. Objective: The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. Design and Participants: We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4–19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. Main Outcome Measures: Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. Results: ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from −4.6 to −3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from −4.6 to −4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. Conclusions: Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

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Two novelCOL1A1 mutations in patients with osteogenesis imperfecta (OI) affect the stability of the collagen type I triple-helix

Journal of Applied Genetics ◽

10.1007/bf03195625 ◽

2008 ◽

Vol 49 (3) ◽

pp. 283-295 ◽

Cited By ~ 12

Author(s):

Joanna Witecka ◽

Aleksandra M. Auguściak-Duma ◽

Anna Kruczek ◽

Anna Szydło ◽

Marta Lesiak ◽

...

Keyword(s):

Osteogenesis Imperfecta ◽

Triple Helix ◽

Collagen Type ◽

Collagen Type I ◽

Type I ◽

The Stability

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Calvaria Bone Transcriptome in Mouse Models of Osteogenesis Imperfecta

International Journal of Molecular Sciences ◽

10.3390/ijms22105290 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5290

Author(s):

Pierre Moffatt ◽

Iris Boraschi-Diaz ◽

Juliana Marulanda ◽

Ghalib Bardai ◽

Frank Rauch

Keyword(s):

Osteogenesis Imperfecta ◽

Mouse Models ◽

Transforming Growth Factor Beta ◽

Collagen Type ◽

Transforming Growth Factor ◽

Collagen Type I ◽

Bone Fragility ◽

Type I ◽

Growth Factor Beta ◽

Upregulated Genes

Osteogenesis imperfecta (OI) is a bone fragility disorder that is usually caused by mutations affecting collagen type I. We compared the calvaria bone tissue transcriptome of male 10-week-old heterozygous Jrt (Col1a1 mutation) and homozygous oim mice (Col1a2 mutation) to their respective littermate results. We found that Jrt and oim mice shared 185 differentially expressed genes (upregulated: 106 genes; downregulated: 79 genes). A total of seven genes were upregulated by a factor of two or more in both mouse models (Cyp2e1, Slc13a5, Cgref1, Smpd3, Ifitm5, Cthrc1 and Rerg). One gene (Gypa, coding for a blood group antigen) was downregulated by a factor of two or more in both OI mouse models. Overrepresentation analyses revealed that genes involved in ‘ossification’ were significantly overrepresented among upregulated genes in both Jrt and oim mice, whereas hematopoietic genes were downregulated. Several genes involved in Wnt signaling and transforming growth factor beta signaling were upregulated in oim mice, but less so in Jrt mice. Thus, this study identified a set of genes that are dysregulated across various OI mouse models and are likely to play an important role in the pathophysiology of this disorder.

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Novel Mutations Within Collagen Alpha1(I) and Alpha2(I) Ligand-Binding Sites, Broadening the Spectrum of Osteogenesis Imperfecta – Current Insights Into Collagen Type I Lethal Regions

Frontiers in Genetics ◽

10.3389/fgene.2021.692978 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kinga Sałacińska ◽

Iwona Pinkier ◽

Lena Rutkowska ◽

Danuta Chlebna-Sokół ◽

Elżbieta Jakubowska-Pietkiewicz ◽

...

Keyword(s):

Ligand Binding ◽

Osteogenesis Imperfecta ◽

Binding Sites ◽

Collagen Type ◽

Genetic Disorder ◽

Fatal Outcome ◽

Collagen Type I ◽

Type I ◽

Sequencing Analysis ◽

Ligand Binding Sites

Osteogenesis imperfecta (OI) is a rare genetic disorder demonstrating considerable phenotypic and genetic heterogeneity. The extensively studied genotype–phenotype correlation is a crucial issue for a reliable counseling, as the disease is recognized at increasingly earlier stages of life, including prenatal period. Based on population studies, clusters in COL1A1 and COL1A2 genes associated with the presence of glycine substitutions leading to fatal outcome have been distinguished and named as “lethal regions.” Their localization corresponds to the ligand-binding sites responsible for extracellular interactions of collagen molecules, which could explain high mortality associated with mutations mapping to these regions. Although a number of non-lethal cases have been identified from the variants located in lethal clusters, the mortality rate of mutations has not been updated. An next generation sequencing analysis, using a custom gene panel of known and candidate OI genes, was performed on a group of 166 OI patients and revealed seven individuals with a causative mutations located in the lethal regions. Patients’ age, ranging between 3 and 25 years, excluded the expected fatal outcome. The identification of non-lethal cases caused by mutations located in lethal domains prompted us to determine the actual mortality caused by glycine substitutions mapping to lethal clusters and evaluate the distribution of all lethal glycine mutations across collagen type I genes, based on records deposited in the OI Variant Database. Finally, we identified six glycine substitutions located in lethal regions of COL1A1 and COL1A2 genes, of which four are novel. The review of all mutations in the dedicated OI database, revealed 33 distinct glycine substitutions in two lethal domains of COL1A1, 26 of which have been associated with a fatal outcome. Similarly, 109 glycine substitutions have been identified in eight lethal clusters of COL1A2, of which 51 have been associated with a fatal manifestation. An analysis of all glycine substitutions leading to fatal phenotype, showed that their distribution along collagen type I genes is not regular, with 17% (26 out of 154) of mutations reported in COL1A1 and 64% (51 out of 80) in COL1A2 corresponding to localization of the lethal regions.

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