A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication

Al-Yassin, Amina; Calder, Alistair; Harrison, Mike; Lester, Tracy; Lord, Helen; Oldridge, Michael; Watkins, Sophie; Keen, Richard; Wakeling, Emma

doi:10.1038/s41431-018-0166-7

Cited by 9 publications

(15 citation statements)

References 15 publications

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“…Both loss-of-function and gain-of-function of Runx2 would result in brachydactyly. It was reported that intragenic duplication encompassing exons 3–5 or 3–6 of Runx2 gene was associated with brachydactyly phenotype [41, 42]. Real-time PCR results showed that Runx2 had a lower expression level in both WT and WT groups compared to the control group.…”

Section: Resultsmentioning

confidence: 99%

p.E95K mutation in Indian hedgehog causing brachydactyly type A1 impairs IHH/Gli1 downstream transcriptional regulation

Shen

Shi

et al. 2019

BMC Genet

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BackgroundBrachydactyly type A1 (BDA1, OMIM 112500) is a rare inherited malformation characterized primarily by shortness or absence of middle bones of fingers and toes. It is the first recorded disorder of the autosomal dominant Mendelian trait. Indian hedgehog (IHH) gene is closely associated with BDA1, which was firstly mapped and identified in Chinese families in 2000. Previous studies have demonstrated that BDA1-related mutant IHH proteins affected interactions with its receptors and impaired IHH signaling. However, how the altered signaling pathway affects downstream transcriptional regulation remains unclear.ResultsBased on the mouse C3H10T1/2 cell model for IHH signaling activation, two recombinant human IHH-N proteins, including a wild type protein (WT, amino acid residues 28–202) and a mutant protein (MT, p.E95k), were analyzed. We identified 347, 47 and 4 Gli1 binding sites in the corresponding WT, MT and control group by chromatin immunoprecipitation and the overlapping of these three sets was poor. The putative cis regulated genes in WT group were enriched in sensory perception and G-protein coupled receptor-signaling pathway. On the other hand, putative cis regulated genes were enriched in Runx2-related pathways in MT group. Differentially expressed genes in WT and MT groups indicated that the alteration of mutant IHH signaling involved cell-cell signaling and cellular migration. Cellular assay of migration and proliferation validated that the mutant IHH signaling impaired these two cellular functions.ConclusionsIn this study, we performed integrated genome-wide analyses to characterize differences of IHH/Gli1 downstream regulation between wild type IHH signaling and the E95K mutant signaling. Based on the cell model, our results demonstrated that the E95K mutant signaling altered Gli1-DNA binding pattern, impaired downstream gene expressions, and leaded to weakened cellular proliferation and migration. This study may help to deepen the understanding of pathogenesis of BDA1 and the role of IHH signaling in chondrogenesis.Electronic supplementary materialThe online version of this article (10.1186/s12863-018-0697-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

p.E95K mutation in Indian hedgehog causing brachydactyly type A1 impairs IHH/Gli1 downstream transcriptional regulation

Shen

Shi

et al. 2019

BMC Genet

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“…Moreover, it has been reported that the duplicated copy number of PTHrP caused BDA1 phenotype [ 34 ]. Recent studies have found that the copy number variation of RUNX2 resulted in brachydactyly-liked phenotypes [ 35 – 37 ]. Taking together, our results indicated that the identified DEMs might be responsible for the pathogenesis of BDA1 by exerting influence on the regulation of Runx1/2.…”

Section: Discussionmentioning

confidence: 99%

Altered microRNAs in C3H10T1/2 cells induced by p.E95K mutant IHH signaling

Zhou

Chen

et al. 2021

Hereditas

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Background Indian Hedgehog (IHH), an important cell signaling protein, plays a key regulatory role in development of cartilage and chondrogenesis. Earlier studies have shown that heterozygous missense mutations in IHH gene may cause brachydactyly type A1 (BDA1), an autosomal dominant inheritance disease characterized by apparent shortness or absence of the middle phalanges of all digits. MicroRNAs (miRNAs) have been found to be significant post-transcriptional regulators of gene expression and significantly influence the process of bone-development. Therefore, it is possible that miRNAs are involved in the mechanism underlying the development of BDA1. However, the relationship between miRNAs and the pathogenesis of BDA1 remains unclear. Methods In this study, we used microarray-based miRNA profiling to investigate the role of miRNAs in BDA1 by characterization of differentially expressed miRNAs in C3H10T1/2 cell line induced by wild type (WT) and p.E95K mutant (MT) IHH signaling. Results Our results identified 6 differentially expressed miRNAs between WT and control (CT) group and 5 differentially expressed miRNAs between MT and CT groups. In particular, miR-135a-1-3p was found to be a significantly differentially expressed miRNA between WT and CT group. Results of dual-luciferase reporter gene experiment successfully discovered Hoxd10 was one of the target gene of miR-135a-1-3p. Additionally, our pathway analysis revealed that the targets of these miRNAs of interest were highly involved with Runx1/2, Notch and collagen-related pathways. Conclusions Taken together, our findings provided important clue for future study of the process of miRNA-regulation in IHH signaling and novel insights into the regulatory role of miRNA in pathogenesis of BDA1.

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“…The distinctive radiological features are shortened or absent clavicles, delayed ossification of the skull bones, and delayed ossification of pelvic bones [ 203 , 204 ]. On the other hand, duplications of the RUNX2 gene are associated with metaphyseal dysplasia with maxillary hypoplasia, characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, and dystrophic teeth [ 205 , 206 ].…”

Section: Transcription Factorsmentioning

confidence: 99%

Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

Guasto

Cormier‐Daire

2021

IJMS

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Bone development is a tightly regulated process. Several integrated signaling pathways including HH, PTHrP, WNT, NOTCH, TGF-β, BMP, FGF and the transcription factors SOX9, RUNX2 and OSX are essential for proper skeletal development. Misregulation of these signaling pathways can cause a large spectrum of congenital conditions categorized as skeletal dysplasia. Since the signaling pathways involved in skeletal dysplasia interact at multiple levels and have a different role depending on the time of action (early or late in chondrogenesis and osteoblastogenesis), it is still difficult to precisely explain the physiopathological mechanisms of skeletal disorders. However, in recent years, significant progress has been made in elucidating the mechanisms of these signaling pathways and genotype–phenotype correlations have helped to elucidate their role in skeletogenesis. Here, we review the principal signaling pathways involved in bone development and their associated skeletal dysplasia.

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A three-generation family with metaphyseal dysplasia, maxillary hypoplasia and brachydactyly (MDMHB) due to intragenic RUNX2 duplication

Cited by 9 publications

References 15 publications

p.E95K mutation in Indian hedgehog causing brachydactyly type A1 impairs IHH/Gli1 downstream transcriptional regulation

p.E95K mutation in Indian hedgehog causing brachydactyly type A1 impairs IHH/Gli1 downstream transcriptional regulation

Altered microRNAs in C3H10T1/2 cells induced by p.E95K mutant IHH signaling

Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

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