<i>MSX2</i>Gene Duplication in a Patient with Eye Development Defects

Plaisancié, Julie; Collet, Corinne; Pelletier, Valérie; Perdomo, Yaumara; Studer, Fouzia; Fradin, Mélanie; Schaefer, Eric; Speeg-Schatz, C.; Bloch‐Zupan, Agnès; Flori, Elisabeth; Dollfus, Hélène

doi:10.3109/13816810.2014.886270

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…Two previous publications ( Aïoub et al, 2007 ; Molla et al, 2010 ) reported that, in the targeted deletion mouse model Msx2 −/− , Msx2 was implicated in both isolated enamel dysplasia (regulating amelogenin, enamelin) and syndromic enamel dysplasia (through alterations in cell-cell junctions). To date one duplication of the entire gene MSX2 has been reported in a syndromic (craniofacial, eye and limb anomalies) individual associated with hypoplastic AI ( Plaisancié et al, 2015 ). No variant in this gene was identified in our cohort.…”

Section: Resultsmentioning

confidence: 99%

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Bloch-Zupan,

Rey,

Jimenez-Armijo

et al. 2023

Front. Physiol.

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Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.

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Section: Resultsmentioning

confidence: 99%

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Bloch-Zupan,

Rey,

Jimenez-Armijo

et al. 2023

Front. Physiol.

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“…Msx2 gene encodes homeoprotein that acts as transcriptional factor binding specific DNA sequences and plays an important role during early skeletal development . In human, gain‐and loss‐of‐function associated with MSX2 mutations are correlated to premature cranial suture fusion (Boston‐type2 craniosynostosis) and impaired suture closing in the parietal foramina . Besides these major skeletal manifestations, in Msx2 transgenic mouse model, tooth root abnormalities and delayed tooth eruption are observed in addition to enamel and cranial suture defects .…”

Section: Introductionmentioning

confidence: 99%

Experimental periodontitis in Msx2 mutant mice induces alveolar bone necrosis

Korah

Amri

Bugueno

et al. 2019

Journal of Periodontology

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Background: Msx2 homeoprotein is a key transcription factor of dental and periodontal tissue formation and is involved in many molecular pathways controlling mineralized tissue homeostasis such as Wnt/sclerostin pathway. This study evaluated the effect of Msx2-null mutation during experimental periodontitis in mice. Methods: Experimental periodontitis was induced for 30 days in wild-type and Msx2knock-in Swiss mice using Porphyromonas gingivalis infected ligatures. In knock-in mice, Msx2 gene was replaced by n-LacZ gene encoding -galactosidase. Periodontal tissue response was assessed by histomorphometry, tartrate-resistant acid phosphatase histoenzymology, -galactosidase, sclerostin immunochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling assay. Expression of Msx2 gene expression was also evaluated in human gingival biopsies using RT-qPCR. Results: During experimental periodontitis, osteonecrosis area and osteoclast numberwere significantly elevated in knock-in mice compared with wild-type mice. Epithelial downgrowth and bone loss was similar. Sclerostin expression in osteocytes appeared to be reduced during periodontitis in knock-in mice. Msx2 expression was detected in healthy and inflamed human gingival tissues.Conclusion: These data indicated that Msx2 pathway influenced periodontal tissue response to experimental periodontitis and appeared to be a protective factor against alveolar bone osteonecrosis. As shown in other inflammatory processes such as atherothrombosis, genes initially characterized in early development could also play an important role in human periodontal pathogenesis. K E Y W O R D Shuman, mice, Msx2, osteonecrosis, periodontitis J Periodontol. 2020;91:693-704.

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“…A gain-of-function mutation in human MSX2 causes autosomal-dominant Boston-type craniosynostosis, characterized by overgrowth of skull bones [164,165], while loss-of-function mutations result in MSX2 haploinsufficiency and lead to reduced ossification of the parietal bones, enlarged parietal foramina and aberrant closure of the sagittal suture [166]. The case of a child with bicoronal synostosis and cutaneous syndactyly, who presented iridal and chorioretinal colobomas due to MSX2 gene duplication has been recently reported [167].…”

Section: Msx2mentioning

confidence: 99%

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

Markitantova

Симирский

2020

IJMS

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Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina.

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MSX2Gene Duplication in a Patient with Eye Development Defects

Cited by 6 publications

References 35 publications

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Experimental periodontitis in Msx2 mutant mice induces alveolar bone necrosis

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

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