Mutations in WNT1 are a cause of osteogenesis imperfecta

Fahiminiya, Somayyeh; Majewski, Jacek; Mort, John S.; Moffatt, Pierre; Glorieux, Francis H.; Rauch, Frank

doi:10.1136/jmedgenet-2013-101567

Cited by 178 publications

(151 citation statements)

References 25 publications

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“…For example, one patient with osteogenesis imperfecta in whom no pathogenic mutation was identified by our TES gene panel turned out to have "highly likely" pathogenic sequence variations in WNT1, which was reported as one of the causative genes for this phenotype after diagnosis by TES in this study. 13 Third, some genetic defects are simply not detectable by TES using an exon-only capture strategy. They include deep intron variants, variants in regulatory/enhancer sequences, indels of nucleotides larger than a certain size, and chromosomal anomalies.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing

Bae

Kim

Lee

et al. 2016

Genetics in Medicine

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Section: Discussionmentioning

confidence: 99%

“…A woman with type III osteogenesis imperfecta was found to harbor compound heterozygous mutations of WNT1 (ref. 13 ) via WES conducted after TES. For another patient, a novel candidate causative gene was identified after TES and is now under further investigation.…”

Section: Assured Clinical Diagnosis (Categories I and Ii)mentioning

confidence: 99%

Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing

Bae

Kim

Lee

et al. 2016

Genetics in Medicine

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“…No Homozygous -severe OI; some have brain malformation; autism, learning difficulties in some (125) Heterozygous -early-onset osteoporosis, normal growth (126) Osteocyte dysfunction PLS3 Plastin 3 ? X-linked early-onset severe osteoporosis without other OI features (126) Mineralization regulation SERPINF1 Pigment epithelium-derived factor Yes Slowly progressively worsening OI; osteoid mineralization defect (no endochondral defect) ( (133) Linker enzyme deficiency XYLT2 Xylosyltransferase II ?…”

Section: Wnt1mentioning

confidence: 99%

Bone Material Properties in Osteogenesis Imperfecta

Bishop

2016

Journal of Bone and Mineral Research

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Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales.

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“…recently, mutations in the WNT1 gene (Winglesstype mmTV integration site family, member 1, bone mass regulator) have been described in patients diagnosed with oi type iV (ref. 16 ). The incidence of oi ranges from 1:25000-40000 (nonlethal forms) to 1:50000 (lethal forms) live births in the world 17 .…”

Section: Introductionmentioning

confidence: 99%

Eight mutations including 5 novel ones in the COL1A1 gene in Czech patients with osteogenesis imperfecta

Hrušková¹,

Fijałkowski²,

Hul³

et al. 2016

BIOMED PAP

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a Background and Aim. Osteogenesis imperfecta (OI), also called brittle bone disease, is a clinically and genetically heterogeneous disorder characterized by decreased bone density. Autosomal dominant forms result from mutations in either the COL1A1 (collagen type I alpha-1 chain) or COL1A2 (collagen type I alpha-2 chain) genes encoding the type I collagen. The aim of this study was to identify mutations and allelic variants of the COL1A1 gene in patients with osteogenesis imperfecta (OI). Methods and Results. Molecular genetic analysis of the COL1A1 gene was performed in a cohort of 34 patients with OI. The DNA samples were analysed by PCR and Sanger sequencing. DNA changes in coding sequences of the gene were compared with Type 1 Collagen Mutation Database. Genetic variants resulting in either quantitatively or structurally defective protein production were found in 6 unrelated patients. Four identified mutations are connected to decreased protein production (Tyr47X, Arg131X, Arg415X, Gln1341X), 2 result in amino acid substitution (Cys61Phe, Pro1186Ala) and the last affects splicing (c.1057-1G>T). Further, one silent mutation (Gly794Gly) was detected. No protein analysis was performed. Conclusion. Of the 8 identified mutations, 5 were novel and have not been reported before. Only one causes substitution of glycine located within the Gly-X-Y triplets in the triple helical domain. Two mutations are located in major ligand binding regions (MLBR) which are important for bone strength and flexibility. Although the genotype-phenotype correlation is still unclear, our findings should contribute to elucidating this relationship in patients diagnosed with OI.

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Mutations in WNT1 are a cause of osteogenesis imperfecta

Abstract: Recessive inactivating mutations in WNT1 are a new cause of OI type IV.

Cited by 178 publications

References 25 publications

Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing

Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing

Bone Material Properties in Osteogenesis Imperfecta

Eight mutations including 5 novel ones in the COL1A1 gene in Czech patients with osteogenesis imperfecta

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