The Experts below are selected from a list of 140477799 Experts worldwide ranked by ideXlab platform
Peter H Byers - One of the best experts on this subject based on the ideXlab platform.
-
recessively inherited forms of osteogenesis imperfecta
2012Co-Authors: Peter H Byers, Shawna M PyottAbstract:More than 90% of people who have osteogenesis imperfecta (OI) have heterozygous mutations in one of the two type I collagen genes, COL1A1 and COL1A2. The effects of these changes range from death in the perinatal period to barely increased fracture frequency and reflect different types of mutations. Introduction of bisphosphonates during the past 20 years has targeted bone fragility by decreased resorption. The recent recognition of biallelic mutations in genes that affect either collagen assembly and processing or the regulation of osteoblast development has raised hopes for therapies that would be specific for single-gene disorders and identify cellular targets in individuals with the dominant forms of OI. These hopes are yet to be met, but the study of the recessively inherited forms of OI has illuminated the details of the collagen processing pathways.
-
mutation and polymorphism spectrum in osteogenesis imperfecta type ii implications for genotype phenotype relationships
2009Co-Authors: Dale L Bodian, Peter H Byers, Tingfung Chan, Annie Poon, Ulrike Schwarze, Kathleen Yang, Puiyan Kwok, Teri E KleinAbstract:Osteogenesis imperfecta (OI), also known as brittle bone disease, is a clinically and genetically heterogeneous disorder primarily characterized by susceptibility to fracture. Although OI generally results from mutations in the type I collagen genes, COL1A1 and COL1A2, the relationship between genotype and phenotype is not yet well understood. To provide additional data for genotype-phenotype analyses and to determine the proportion of mutations in the type I collagen genes among subjects with lethal forms of OI, we sequenced the coding and exon-flanking regions of COL1A1 and COL1A2 in a cohort of 63 subjects with OI type II, the perinatal lethal form of the disease. We identified 61 distinct heterozygous mutations in type I collagen, including five non-synonymous rare variants of unknown significance, of which 43 had not been seen previously. In addition, we found 60 SNPs in COL1A1, of which 17 were not reported previously, and 82 in COL1A2, of which 18 are novel. In three samples without collagen mutations, we found inactivating mutations in CRTAP and LEPRE1, suggesting a frequency of these recessive mutations of approximately 5% in OI type II. A computational model that predicts the outcome of substitutions for glycine within the triple helical domain of collagen alpha1(I) chains predicted lethality with approximately 90% accuracy. The results contribute to the understanding of the etiology of OI by providing data to evaluate and refine current models relating genotype to phenotype and by providing an unbiased indication of the relative frequency of mutations in OI-associated genes.
-
gene targeting of mutant COL1A2 alleles in mesenchymal stem cells from individuals with osteogenesis imperfecta
2008Co-Authors: Joel R Chamberlain, Peter H Byers, Ulrike Schwarze, David R Deyle, Peirong Wang, Roli K Hirata, David W RussellAbstract:Mesenchymal stem cells (MSCs) are adult cells with the capacity to differentiate into multiple cell types, including bone, fat, cartilage, and muscle cells. In order to effectively utilize autologous MSCs in cell-based therapies, precise genetic manipulations are required to eliminate the effects of disease-causing mutations. We previously used adeno-associated virus (AAV) vectors to target and inactivate mutant COL1A1 genes in MSCs from individuals with the brittle bone disorder, osteogenesis imperfecta (OI). Here we have used AAV vectors to inactivate mutant COL1A2 genes in OI MSCs, thereby demonstrating that both type I collagen genes responsible for OI can be successfully targeted. We incorporated improved vector designs so as to minimize the consequences of random integration, facilitate the removal of potential antigens, and avoid unwanted exon skipping. MSCs targeted at mutant COL1A2 alleles produced normal type I procollagen and formed bone, thereby demonstrating their therapeutic potential.
-
partial COL1A2 gene duplication produces features of osteogenesis imperfecta and ehlers danlos syndrome type vii
2000Co-Authors: Michael L Raff, W J Craigen, Lynne T Smith, Douglas R Keene, Peter H ByersAbstract:Type I collagen is the most abundant structural protein in the mammalian body. It exists as a heterotrimer of two subunits in the form [α1(I)]2α2(I). Pathogenic mutations in COL1A1 and COL1A2, the genes that encode the two subunits, cause a range of phenotypes including mild to lethal forms of osteogenesis imperfecta and a restricted set of Ehlers-Danlos syndrome phenotypes. Lethal mutations usually result from missense mutations that disrupt the normal triple helical structure of the molecule. Multi-exon duplication or deletion in type I collagen genes has rarely been observed and has generally resulted in a lethal or severe phenotype. We report a partial duplication in the COL1A2 gene that causes a relatively mild phenotype, despite the addition of 477 amino acids to the triple helical domain of the proα2(I) chain. The abnormal molecule is synthesized and secreted by cultured dermal fibroblasts in a normal fashion. Electron microscopy of dermal tissue reveals small but otherwise near normal collagen fibrils. The gene duplication occurred by mitotic sister chromatid exchange in the mother who is mosaic for the duplication allele. Examination of the abnormal sequence suggests a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.
-
osteogenesis imperfecta type iii mutations in the type i collagen structural genes col1a1 and COL1A2 are not necessarily responsible
1993Co-Authors: G A Wallis, Peter H Byers, Bryan Sykes, C G Mathew, Denis Viljoen, Peter BeightonAbstract:Most forms of osteogenesis imperfecta are caused by dominant mutations in either of the two genes, COL1A1 and COL1A2, that encode the pro alpha 1(I) and pro alpha 2(I) chains of type I collagen, respectively. However, a severe, autosomal recessive form of OI type III with a comparatively high frequency has been recognised in the black populations of southern Africa. We preformed linkage analyses in eight OI type III families using RFLPs associated with the COL1A1 and COL1A2 loci to determine whether mutations in the genes for type I collagen were responsible for this form of OI. Recombination between the OI phenotype and polymorphic markers at both loci was shown in three of the eight families investigated. The combined lod scores for the eight families were -10.6 for COL1A1 and -11.2 for COL1A2. Further, we examined the type I procollagen produced by skin fibroblast cultures derived from 15 affected and 12 unaffected subjects from the above eight families plus one further family. We found no evidence for defects in the synthesis, structure, secretion, or post-translational modification of the chains of type I procollagen produced by any of the family members. These results suggest that mutations within or near the type I collagen structural genes are not responsible for this form of OI.
Andreas Kindmark - One of the best experts on this subject based on the ideXlab platform.
-
Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta – A retrospective cohort study
2017Co-Authors: Kristofer Andersson, Andreas Kindmark, Katarina Lindahl, Eva Astrom, Göran Dahllöf, Giedre Grigelioniene, Barbro MalmgrenAbstract:Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p.Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p.Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.
-
allele dependent silencing of collagen type i using small interfering rnas targeting 3 utr indels a novel therapeutic approach in osteogenesis imperfecta
2013Co-Authors: Katarina Lindahl, Carljohan Rubin, Andreas Kindmark, Navya Laxman, Eva Astrom, Osten LjunggrenAbstract:Osteogenesis imperfecta, also known as “brittle bone disease”, is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3’UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3’UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta.
-
allele dependent silencing of collagen type i using small interfering rnas targeting 3 prime utr indels ndash a novel therapeutic approach in osteogenesis imperfecta
2013Co-Authors: Katarina Lindahl, Carljohan Rubin, Andreas Kindmark, Navya Laxman, Eva Astrom, Osten LjunggrenAbstract:Introduction: Osteogenesis imperfecta (OI) is a heterogenous disease of connective tissue, usually caused by dominant mutations in the genes encoding collagen I, COL1A1 and COL1A2 respectively. Severe forms are lethal, often due to thoracic fractures and intracerebral hemorrhaging. Bisphosphonates are generally the drug of choice, but the effect is neither sufficient nor satisfactory. A promising field is gene silencing through RNA interference, as silencing of the mutated allele would convert a severe OI to a mild OI type I in the case of a COL1A1 mutation and to a phenotypically normal patient in the case of a COL1A2 mutation. However, more than 800 different mutations have been described and creating unique small interfering RNAs (siRNAs), each targeting one mutation would be labour intensive. In this study allele preferential siRNAs were used to target two common 3′ untranslated region insertion/deletions (3′UTR indels) in COL1A1 and COL1A2 in a mutation independent approach. Method: Allele frequencies of the 3′UTR indels were determined in a cohort of 96 healthy individuals and in 96 patients with OI. Four siRNAs targeting each allele of the indels in COL1A1 and COL1A2 were designed and tested in various concentrations in cultures of primary bone derived cells using magnet-assisted transfection (MATRA). RNA was prepared 72 h post transfection and cDNA was created and sequenced. The software PeakPicker was used for calculations of insertion/non-insertion allele ratios. siRNA results were normalized to cell populations treated with negative control siRNAs. Quantitative PCR was used to determine the collagen type I mRNA abundances in treated and negative control treated cell populations. Results: Approximately 50% of individuals genotyped were heterozygous for each of the indels and thus potential candidates for therapy. Allele dependent silencing was observed, with the most promising results for siRNAs complementary to the insertion harbouring alleles. The allele ratio was shifted from 1 to 0.21 and 0.19 for COL1A1 and COL1A2 respectively at the highest concentration used. A slightly lower concentration rendered the ratios 0.21 and 0.34 and an appropriate reduction in mRNA abundance was subsequently demonstrated. This shift represents an increase in normal fibrils from 25 to 69% in COL1A1 and 50 to 75% in COL1A2. In conclusion allele dependent silencing of collagen type I utilizing indels is a promising mutation independent approach for OI.
-
col1 c propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta
2011Co-Authors: Katarina Lindahl, Carljohan Rubin, Elena Makareeva, Aileen M Barnes, Nadja Fratzlzelman, Michael P Whyte, Theresa E Hefferan, Marina Brusel, Michael J Yaszemski, Andreas KindmarkAbstract:Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA Z-score was +3.9 and pQCT vBMD was+3.1; Patient 2 had L1-L4 DXA Z-score of 0.0 and pQCT vBMD of -1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FTIR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2's bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization.
-
allele dependent silencing of COL1A2 using small interfering rnas
2008Co-Authors: Katarina Lindahl, Carljohan Rubin, Andreas Kindmark, Osten LjunggrenAbstract:Osteogenesis imperfecta (OI) is generally caused by a dominant mutation in Collagen I, encoded by the genes COL1A1 and COL1A2. To date there is no satisfactory therapy for OI, but inactivation of the mutant allele through small interfering RNAs (siRNA) is a promising approach, as siRNAs targeting each allele of a polymorphism could be used for allele-specific silencing irrespective of the location of the actual mutations. In this study we examined the allele dependent effects of several tiled siRNAs targeting a region surrounding an exonic COL1A2 T/C polymorphism (rs1800222) in heterozygous primary human bone cells. Relative abundances of COL1A2 alleles were determined by cDNA sequencing and overall COL1A2 abundance was analyzed by quantitative PCR. One of the siRNAs decreased overall COL1A2 abundance by 71% of which 75% was due to silencing of the targeted T-allele. In conclusion, allele-preferential silencing of Collagen type I genes may be a future therapeutic approach for OI.
Leena Alakokko - One of the best experts on this subject based on the ideXlab platform.
-
heterozygous mutations in the ldl receptor related protein 5 lrp5 gene are associated with primary osteoporosis in children
2005Co-Authors: Heini Hartikka, Leena Alakokko, Outi Makitie, Minna Mannikko, Andrea S Doria, Alan Daneman, William G Cole, Etienne SochettAbstract:Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis. Introduction: The gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5) gene has recently been shown to affect bone mass accrual during growth and to be involved in osteoporosis-pseudoglioma syndrome and a high bone mass phenotype. Mutations in the type I collagen genes (COL1A1 and COL1A2) are known to cause osteogenesis imperfecta, characterized by increased bone fragility. Materials and Methods: Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations. Results and Conclusions: No mutations were detected in the type I collagen genes, but two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) were found in the LRP5 gene in three of the patients. The frameshift mutation was also seen in the proband's father and brother, who both were found to have significant osteoporosis. R1036Q was observed in the proband's mother and two brothers, who all had osteoporosis. These results indicate that heterozygous mutations in the LRP5 gene can cause osteoporosis in both children and adults.
-
lack of correlation between the type of col1a1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients
2004Co-Authors: Heini Hartikka, Kaija Kuurila, Jarmo Korkko, Ilkka Kaitila, Reidar Grenman, Seppo Pynnonen, James Hyland, Leena AlakokkoAbstract:Osteogenesis imperfecta (OI) is caused by mutations in COL1A1 and COL1A2 that code for the alpha1 and alpha2 chains of type I collagen. Phenotypes correlate with the mutation types in that COL1A1 null mutations lead to OI type I, and structural mutations in alpha1(I) or alpha2(I) lead to more severe OI types (II-IV). However, correlative analysis between mutation types and OI associated hearing loss has not been previously performed. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed here for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. The 49 mutations represented the molecular genetic background of 41.1% of the Finnish OI population. A total of 38 mutations were in COL1A1 and 11 were in COL1A2. Of these, 16 were glycine substitutions and 16 were splicing mutations in alpha1(I) or alpha2(I). In addition, 17 null allele mutations were detected in COL1A1. A total of 32 patients (65.3%) with a mutation had hearing loss. That is slightly more than in our previous population study on Finnish adults with OI (57.9%). The association between the mutation types and OI type was statistically evident. Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. However, no correlation was found between the mutated gene or mutation type and hearing pattern. These results suggest that the basis of hearing loss in OI is complex, and it is a result of multifactorial, still unknown genetic effects.
-
analysis of the col1a1 and COL1A2 genes by pcr amplification and scanning by conformation sensitive gel electrophoresis identifies only col1a1 mutations in 15 patients with osteogenesis imperfecta type i identification of common sequences of null allele mutations
1998Co-Authors: Lieve Nuytinck, Anne De Paepe, Jarmo Korkko, Leena Alakokko, James J Earley, Darwin J ProckopAbstract:Although >90% of patients with osteogenesis imperfecta (OI) have been estimated to have mutations in the COL1A1 and COL1A2 genes for type I procollagen, mutations have been difficult to detect in all patients with the mildest forms of the disease (i.e., type I). In this study, we first searched for mutations in type I procollagen by analyses of protein and mRNA in fibroblasts from 10 patients with mild OI; no evidence of a mutation was found in 2 of the patients by the protein analyses, and no evidence of a mutation was found in 5 of the patients by the RNA analyses. We then searched for mutations in the original 10 patients and in 5 additional patients with mild OI, by analysis of genomic DNA. To assay the genomic DNA, we established a consensus sequence for the first 12 kb of the COL1A1 gene and for 30 kb of new sequences of the 38-kb COL1A2 gene. The sequences were then used to develop primers for PCR for the 103 exons and exon boundaries of the two genes. The PCR products were first scanned for heteroduplexes by conformation-sensitive gel electrophoresis, and then products containing heteroduplexes were sequenced. The results detected disease-causing mutations in 13 of the 15 patients and detected two additional probable disease-causing mutations in the remaining 2 patients. Analysis of the data developed in this study and elsewhere revealed common sequences for mutations causing null alleles.
Francis H Glorieux - One of the best experts on this subject based on the ideXlab platform.
-
dna sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta diagnostic yield and mutation spectrum
2016Co-Authors: Ghalib Bardai, Francis H Glorieux, Pierre Moffatt, Frank RauchAbstract:We detected disease-causing mutations in 585 of 598 individuals (98 %) with typical features of osteogenesis imperfecta (OI). In mild OI, only collagen type I encoding genes were involved. In moderate to severe OI, mutations in 12 different genes were found; 11 % of these patients had mutations in recessive genes. OI is usually caused by mutations in COL1A1 or COL1A2, the genes encoding collagen type I alpha chains, but mutations in at least 16 other genes have also been associated with OI. It is presently unknown what proportion of individuals with clinical features of OI has a disease-causing mutation in one of these genes. DNA sequence analysis was performed on 598 individuals from 487 families who had a typical OI phenotype. OI type I was diagnosed in 43 % of individuals, and 57 % had moderate to severe OI, defined as OI types other than type I. Disease-causing variants were detected in 97 % of individuals with OI type I and in 99 % of patients with moderate to severe OI. All mutations found in OI type I were dominant and exclusively affected COL1A1 or COL1A2. In moderate to severe OI, dominant mutations were found in COL1A1/COL1A2 (77 %), IFITM5 (9 %), and P4HB (0.6 %). Mutations in one of the recessive OI-associated gene were observed in 12 % of individuals with moderate to severe OI. The genes most frequently involved in recessive OI were SERPINF1 (4.0 % of individuals with moderate to severe OI) and CRTAP (2.9 %). DNA sequence analysis of currently known OI-associated genes identifies disease-causing variants in almost all individuals with a typical OI phenotype. About 20 % of individuals with moderate to severe OI had mutations in genes other than COL1A1/COL1A2.
-
scoliosis in osteogenesis imperfecta caused by col1a1 COL1A2 mutations genotype phenotype correlations and effect of bisphosphonate treatment
2016Co-Authors: Francis H Glorieux, Atsuko Sato, Jean Ouellet, Takeshi Muneta, Frank RauchAbstract:Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type.
-
mutations in wnt1 are a cause of osteogenesis imperfecta
2013Co-Authors: Somayyeh Fahiminiya, Francis H Glorieux, Pierre Moffatt, Jacek Majewski, John S Mort, Frank RauchAbstract:Background Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually due to dominant mutations in COL1A1 or COL1A2 . Rare recessive forms of OI, caused by mutations in genes involved in various aspects of bone formation, have been described as well. Objective To identify the cause of OI in eight children with severe bone fragility and a clinical diagnosis of OI type IV who had had negative results on COL1A1 / COL1A2 Sanger sequencing. Methods Whole exome sequencing was performed in genomic DNA samples from all eight individuals. Results WNT1 mutations were found in four children from three families. WNT1 was the only gene where mutations were found in all of these four patients. Two siblings from a consanguineous family had a homozygous missense mutation affecting a highly conserved cysteine residue in WNT1 (c.428G>T (p.Cys143Phe)). One girl had a homozygous frameshift deletion (c.287\_300del(p.Gln96Profs)). A girl from a third family was compound heterozygous for a frameshift insertion and a missense mutation affecting a conserved amino acid (c.946\_949insAACA (p.Ser317Lysfs); c.1063G>T (p.Val355Phe)). All of these children had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life. The Wnt signalling pathway is one of the key regulators of osteoblast activity. Conclusions Recessive inactivating mutations in WNT1 are a new cause of OI type IV.
-
Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta.
2011Co-Authors: I Mouna Ben Amor, Francis H Glorieux, Frank RauchAbstract:Osteogenesis imperfecta, discussed in Baldridge et al. 2008 is an inherited bone fragility disorder with a wide range of clinical severity that in the majority of cases is caused by mutations in COL1A1 or COL1A2, the genes that encode the two collagen type I alpha chains. Here we describe genotype-phenotype correlations in OI patients who have mutations affecting collagen type I. This paper is based on findings in a large single-centre OI population and a review of the literature.
-
thirty three novel col1a1 and COL1A2 mutations in patients with osteogenesis imperfecta types i iv
2001Co-Authors: Leanne M Ward, Francis H Glorieux, Ljiljana Lalic, Peter J RoughleyAbstract:Osteogenesis imperfecta (OI) is a heritable disease of bone characterized by low bone mass and bone fragility. Six different types of OI have been described to date, based on clinical phenotype and histological findings. The genetic defect in many patients with OI types I-IV is due to mutations in the genes encoding type I collagen, while patients with OI types V and VI show no evidence of mutations in the COL1A1/COL1A2 genes. Here we report thirty-three novel mutations in patients with types I-IV OI. Sixteen mutations were in COL1A1 and seventeen were in COL1A2. Most mutations resulted in substitutions for glycine: one of these, a doublet GG>CC transversion, created a unique Gly-->Pro missense mutation in the triple helical domain of COL1A2. Two rare triple helical Gly-->Glu substitutions in COL1A2 are also described. In addition, there were six single-base deletion mutations resulting in frameshifts, seven splice junction mutations, and a 9-bp triple helix insertion associated with a severe (OI II) phenotype. The variety of mutations described in the COL1A1/COL1A2 genes giving rise to an OI phenotype is in accordance with the clinical heterogeneity of the disease. Hum Mutat 17:434, 2001.
Aare Martson - One of the best experts on this subject based on the ideXlab platform.
-
mutational analysis of col1a1 and COL1A2 genes among estonian osteogenesis imperfecta patients
2017Co-Authors: Lidiia Zhytnik, Katre Maasalu, Ele Prans, Ene Reimann, Aare Martson, Sulev KoksAbstract:Osteogenesis imperfecta (OI) is a rare bone disorder. In 90% of cases, OI is caused by mutations in the COL1A1/2 genes, which code procollagen α1 and α2 chains. The main aim of the current research was to identify the mutational spectrum of COL1A1/2 genes in Estonian patients. The small population size of Estonia provides a unique chance to explore the collagen I mutational profile of 100% of OI families in the country. We performed mutational analysis of peripheral blood gDNA of 30 unrelated Estonian OI patients using Sanger sequencing of COL1A1 and COL1A2 genes, including all intron-exon junctions and 5′UTR and 3′UTR regions, to identify causative OI mutations. We identified COL1A1/2 mutations in 86.67% of patients (26/30). 76.92% of discovered mutations were located in the COL1A1 (n = 20) and 23.08% in the COL1A2 (n = 6) gene. Half of the COL1A1/2 mutations appeared to be novel. The percentage of quantitative COL1A1/2 mutations was 69.23%. Glycine substitution with serine was the most prevalent among missense mutations. All qualitative mutations were situated in the chain domain of pro-α1/2 chains. Our study shows that among the Estonian OI population, the range of collagen I mutations is quite high, which agrees with other described OI cohorts of Northern Europe. The Estonian OI cohort differs due to the high number of quantitative variants and simple missense variants, which are mostly Gly to Ser substitutions and do not extend the chain domain of COL1A1/2 products.
-
mutation analysis of the col1a1 and COL1A2 genes in vietnamese patients with osteogenesis imperfecta
2016Co-Authors: Binh Ho Duy, Lidiia Zhytnik, Katre Maasalu, Ivo Kandla, Ele Prans, Ene Reimann, Aare MartsonAbstract:The genetics of osteogenesis imperfecta (OI) have not been studied in a Vietnamese population before. We performed mutational analysis of the COL1A1 and COL1A2 genes in 91 unrelated OI patients of Vietnamese origin. We then systematically characterized the mutation profiles of these two genes which are most commonly related to OI. Genomic DNA was extracted from EDTA-preserved blood according to standard high-salt extraction methods. Sequence analysis and pathogenic variant identification was performed with Mutation Surveyor DNA variant analysis software. Prediction of the pathogenicity of mutations was conducted using Alamut Visual software. The presence of variants was checked against Dalgleish’s osteogenesis imperfecta mutation database. The sample consisted of 91 unrelated osteogenesis imperfecta patients. We identified 54 patients with COL1A1/2 pathogenic variants; 33 with COL1A1 and 21 with COL1A2. Two patients had multiple pathogenic variants. Seventeen novel COL1A1 and 10 novel COL1A2 variants were identified. The majority of identified COL1A1/2 pathogenic variants occurred in a glycine substitution (36/56, 64.3 %), usually serine (23/36, 63.9 %). We found two pathogenic variants of the COL1A1 gene c.2461G > A (p.Gly821Ser) in four unrelated patients and one, c.2005G > A (p.Ala669Thr), in two unrelated patients. Our data showed a lower number of collagen OI pathogenic variants in Vietnamese patients compared to reported rates for Asian populations. The OI mutational profile of the Vietnamese population is unique and related to the presence of a high number of recessive mutations in non-collagenous OI genes. Further analysis of OI patients negative for collagen mutations, is required.