Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia

Kim, Su Jin; Biegański, Tadeusz; Sohn, Young Bae; Kozlowski, K.; Semënov, Mikhail; Okamoto, Nobuhiko; Kim, Chi Hwa; Ko, Ah-Ra; Ahn, Geung Hwan; Choi, Yoon–La; Park, Sung Won; Ki, Chang‐Seok; Kim, Ok-Hwa; Nishimura, Gen; Unger, Sheila; Superti‐Furga, Andrea; Jin, Dong‐Kyu

doi:10.1007/s00439-011-0947-3

Cited by 76 publications

(44 citation statements)

References 19 publications

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“…The marked prognathism displayed by our patient 2 resembles that observed in sclerosteosis (OMIM 269500), van Buchem disease (OMIM 239100), or craniodiaphyseal dysplasia (OMIM 122860), the most severe and lethal form of craniotubular dysplasia, which are all caused by SOST deficiency (Kim et al, 2011). Although no functional link between SOST and PTDSS1 has yet been established, the phenotypic overlap suggests activation of Wnt signaling pathway, which normally promotes bone formation, and underlies high bone mass disorders (MacFarlane et al, 2017).…”

Section: Discussionsupporting

confidence: 58%

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

Piard

Lespinasse

Vlčková

et al. 2018

American J of Med Genetics Pt A

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The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz–Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.

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Section: Discussionsupporting

confidence: 58%

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

Piard

Lespinasse

Vlčková

et al. 2018

American J of Med Genetics Pt A

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“…Mutation of Val21 in the signal peptide of SOST to either Leu or Met significantly diminished SOST secretion. These mutations were documented in two unrelated individuals with this disorder but were not found in samples from healthy patients (252).…”

Section: Sclerostinmentioning

confidence: 89%

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

2013

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The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. Keywords: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

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“…24 Heterozygous SOST mutations have been documented also in CDD affected individuals in Poland. 27 Apart from sclerosteosis 1, van Buchem disease, and CDD, no other simple genetic disorders are known to be associated with mutations in SOST. However, phenotypically similar sclerosteosis 2 may be caused by a mutation of LRP4 (low density lipoprotein receptor-related protein 4) that is involved in sclerostin signal transduction (MIM 614305).…”

Section: Diseases Related To Genetic Disorders Of Sclerostinmentioning

confidence: 99%

Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders

Pietrzyk¹,

Smertka²,

Chudek³

2017

Adv Clin Exp Med

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Sclerostin is a glycoprotein involved in the regulation of bone metabolism, exclusively secreted by osteocytes. It affects the activity of bone morphogenetic proteins (BMPs) and is an inhibitor of the Wnt/β-catenin metabolic pathway in bone cells. Osteocytes reduce the release of sclerostin in response to mechanical stimuli acting on bone, and thus promote the activation of osteogenic pathway Wnt/β-catenin in osteoblasts. This signaling pathway plays a key role in osteogenesis and bone turnover. Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease. Additionally, experimental and clinical studies suggest that sclerostin may promote vascular calcification. Antibodies directed against sclerostin stimulate bone formation and represent a new therapeutic option in the treatment of diseases with increased bone resorption, such as osteoporosis and inflammatory diseases where there is generalized bone loss, periarticular osteoporosis, and cartilage damage, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and glucocorticoid-induced osteoporosis (GIO). Antibody use has the potential to offer new therapeutic approaches in the therapy of mineral and bone disorders resulting from chronic kidney disease (CKD-MBD) and vascular calcifications.

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Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia

Cited by 76 publications

References 19 publications

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders

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