Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in <i><scp>MMP9</scp></i> identified by exome sequencing

Sharony, Reuven; Borochowitz, Zvi; Cohen, Lior; Shtorch-Asor, Atalia; Rosenfeld, R.G.; Modai, Shira; Reinstein, Eyal

doi:10.1111/cge.13020

Cited by 8 publications

(6 citation statements)

References 10 publications

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“…Novel featured bilateral corner fractures in both femurs and wrist that resolved over time [5]. A similar clinical scenario is typical for metaphyseal anadysplasia, a disease that is characterized by severe metaphyseal changes during growth, which resolve spontaneously upon skeletal maturation [29,30]. Interestingly, both these diseases have a defective ECM in common.…”

Section: Accepted Manuscriptmentioning

confidence: 87%

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Costantini

Valta

Baratang

et al. 2019

Bone

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Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with "corner fractures" (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of "corner fractures". An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extra cellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and "corner fracture" appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.

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Section: Accepted Manuscriptmentioning

confidence: 87%

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Costantini

Valta

Baratang

et al. 2019

Bone

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“…It is important to note that most human MMP9 mutations are examined from an oncological perspective as they can be associated with increased risk of cancer metastasis. [24][25][26] To the best of our knowledge, Mmp9-null mice have not been examined for craniofacial bone defects, but they have been used to model defective osteoclast function. 27,28 Patients with a mutation in CTSK can have the skeletal disorder pycnodysostosis.…”

Section: Discussionmentioning

confidence: 99%

“…A lower jaw phenotype has not been described in patients with metaphyseal anadysplasia. It is important to note that most human MMP9 mutations are examined from an oncological perspective as they can be associated with increased risk of cancer metastasis 24–26 . To the best of our knowledge, Mmp9 ‐null mice have not been examined for craniofacial bone defects, but they have been used to model defective osteoclast function 27,28 …”

Section: Discussionmentioning

confidence: 99%

Treatment with an inhibitor of matrix metalloproteinase 9 or cathepsin K lengthens embryonic lower jaw bone

Houchen

Castro

Leat

et al. 2023

Orthod Craniofacial Res

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Objectives Skeletal malocclusions are common, and severe malocclusions are treated by invasive surgeries. Recently, jaw bone length has been shown to be developmentally controlled by osteoclasts. Our objective was to determine the effect of inhibiting osteoclast‐secreted proteolytic enzymes on lower jaw bone length of avian embryos by pharmacologically inhibiting matrix metalloproteinase‐9 (MMP9) or cathepsin K (CTSK). Methods Quail (Coturnix coturnix japonica) embryos were given a single dose of an inhibitor of MMP9 (iMMP9), an inhibitor CTSK (iCTSK), or vehicle at a developmental stage when bone deposition is beginning to occur. At a developmental stage when the viscerocranium is largely calcified, the heads were scanned via micro‐computed tomography and reproducible landmarks were placed on 3D‐reconstructed skulls; the landmark coordinates were used to quantify facial bone dimensions. Results Approximately half of the quail given either iMMP9 or iCTSK demonstrated an overt lower jaw phenotype, characterized by longer lower jaw bones and a greater lower to upper jaw ratio than control embryos. Additionally, iMMP9‐treated embryos exhibited a significant change in midface length and iCTSK‐treated embryos had significant change in nasal bone length. Conclusion MMP9 and CTSK play a role in osteoclast‐mediated determination of lower jaw bone length. Pharmacological inhibition of MMP9 or CTSK may be a promising therapeutic alternative to surgery for treating skeletal jaw malocclusions, but more preclinical research is needed prior to clinical translation.

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“…Such observation has been reported in patients with some other osteochondrodysplasias, including spondylometaphyseal dysplasia with “corner fractures” caused by mutations in the fibronectin gene and metaphyseal anadysplasia caused by mutations in metalloproteinases. ( 48–51 ) Interestingly, incomplete penetrance and variable expression among patients with identical mutations is a common feature in ribosomopathies, ( 8 ) but the underlying mechanisms still remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia

Costantini

Alm

Tonelli

et al. 2020

Journal of Bone and Mineral Research

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Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation‐positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient‐derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation‐positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR‐Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD‐RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

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Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing

Cited by 8 publications

References 10 publications

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Treatment with an inhibitor of matrix metalloproteinase 9 or cathepsin K lengthens embryonic lower jaw bone

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia

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