Mutations in WNT1 Cause Different Forms of Bone Fragility

Keupp, Katharina; Beleggia, Filippo; Kayserili, Hülya; Barnes, Aileen M.; Steiner, Magdalena; Semler, Oliver; Fischer, Björn; Yiğit, Gökhan; Janda, Claudia Y.; Becker, Jutta; Breer, S.; Altunoğlu, Umut; Grünhagen, Johannes; Krawitz, Peter; Hecht, Jochen; Schinke, Thorsten; Makareeva, Elena; Lausch, Ekkehart; Çankaya, Tufan; Caparrós-Martín, José A.; Lapunzina, Pablo; Temtamy, Samia; Aglan, Mona; Zabel, Bernhard; Eysel, Peer; Koerber, Friederike; Leikin, Sergey; García, K. Christopher; Netzer, Christian; Schönaü, Eckhard; Ruiz‐Pérez, Víctor L.; Mundlos, Stefan; Amling, Michael; Kornak, Uwe; Marini, Joan C.; Wollnik, Bernd

doi:10.1016/j.ajhg.2013.02.010

Cited by 247 publications

(235 citation statements)

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“…Heterozygous WNT1 mutations lead to osteoporosis 16,[98][99][100] . WNT1 interacts with the receptor Frizzled and its co receptor low density lipo protein receptor related protein 5/6 (LRP5/6) to activate bone formation 101,102 (FIG.…”

Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

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504

582

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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%

“…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 ? Vertebral fractures, cataracts, heart defects (134) The noncollagenous proteins within bone have been suggested to have a range of functions, from the formation of collagen fibrils and initiation of mineral platelet formation, to mineral maturation and collagen cross-linking.…”

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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“…The investigation of rare mendelian disorders with decreased BMD as a key diagnostic feature constitutes a strategy for identifying genetic determinants of osteoporosis. [3][4][5][6][7] We identified families with X-linked osteoporosis and fractures among patients with negative tests for the genes encoding collagen type Iα1 and type Iα2 (COL1A1 and COL1A2, respectively) who had been referred to us for diagnosis or ruling out of osteogenesis imperfecta type I. Osteoporosis with fractures as an X-linked trait has been reported by Sillence. 8 We now report data from five families with X-linked osteoporosis and fractures related to pathogenic variants in the gene for plastin 3 (PLS3), provide functional evidence that PLS3 is a bone-regulatory protein, and describe a rare variant or single-nucleotide polymorphism (SNP) associated with decreased BMD and an increased risk of fracture among heterozygous women in the general population.…”

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confidence: 99%