<scp><i>ANO5</i></scp>‐associated Gnathodiaphyseal dysplasia with calvarial doughnut lesions: First report in an Asian Indian with an expanded phenotype

Sandal, Sapna; Arora, Veronica; Verma, Ishwar C.

doi:10.1111/cga.12391

Cited by 4 publications

(4 citation statements)

References 6 publications

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“…Recent studies have reported that serum ALP levels in GDD patients with p.Arg597Ile, p.Ser500Phe, and p.Gly518Glu mutations were elevated. (15,16,18) In this study, we found increased ALP levels in serum and in cultured Ano5 KI/KI mCOBs, suggesting that the p.Cys360Tyr mutation is likely to have an impact on osteoblastogenesis. The expression of mineralization markers was obviously elevated in Ano5 KI/KI osteoblast cultures during osteoblastic differentiation.…”

Section: Discussionsupporting

confidence: 51%

“…(8)(9)(10)(11) Heretofore, 11 missense mutations in the ANO5 gene have been identified to be associated with GDD from various races and ethnicities. (7,(12)(13)(14)(15)(16)(17)(18) Two of them, C356R and C356G, were first reported in a large Japanese family and resulted in reduced cell adhesion and more rounded cell morphology owing to the regulation of intracellular calcium homeostasis. (7) The T513I mutation in ANO5 protein caused a gain of function enabling CaCCs and phospholipid scrambling at low cytosolic Ca 2+ levels.…”

Section: Introductionmentioning

confidence: 99%

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Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia

Wang

Chen

et al. 2020

Journal of Bone and Mineral Research

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Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease characterized by the osteosclerosis of tubular bones and the formation of cemento-osseous lesions in mandibles. Although genetic mutations for GDD have been identified in the ANO5/ TMEM16E gene, the cellular and molecular mechanisms behind the pathogenesis of GDD remain unclear. Here, we generated the first knock-in mouse model for GDD with the expression of human mutation p.Cys360Tyr in ANO5. Homozygous Ano5 knock-in mice (Ano5 KI/KI ) replicated GDD-like skeletal features, including massive jawbones, bowing tibia, bone fragility, sclerosis, and cortical thickening of the femoral and tibial diaphysis. Serum alkaline phosphatase (ALP) levels were elevated in Ano5 KI/KI mice as in GDD patients with p.Cys360Tyr mutation. Calvaria-derived Ano5 KI/KI osteoblast cultures showed increased osteoblastogenesis, including hypermineralized bone matrix and enhanced bone formation-related factors expression. Interestingly, Ano5 KI/KI bone marrow-derived macrophage cultures showed decreased osteoclastogenesis, and Ano5 KI/KI osteoclasts exhibited disrupted actin ring formation, which may be associated with some signaling pathways. In conclusion, this new mouse model may facilitate elucidation of the pathogenesis of GDD and shed more light on its treatment.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia

Wang

Chen

et al. 2020

Journal of Bone and Mineral Research

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“…While we failed to collect biochemical index of 25(OH)D 3 from in the Han GDD patient, Ano5 KI/KI mice manifested higher calcitriol levels in serum and Cyp27b1 expression in kidneys than wild type mice, which indicated that the generation of calcitriol from 25(OH)D 3 was facilitated. Importantly, serum 25(OH)D 3 concentration, one of the most reliable biomarkers of calcitriol metabolic status, is decreased in GDD patients caused by p.Ser500Phe and p.Arg597Ile mutations in ANO5, which is a manifestation of increased calcitriol synthesis (14,49). It is worth noting that calcitriol is involved in calcium reabsorption and mineral deposition by activating calcium channels so as to play a vital role in bone regeneration.…”

Section: Discussionmentioning

confidence: 99%

Integration of metabolomics and transcriptomics provides insights into enhanced osteogenesis in Ano5Cys360Tyr knock-in mouse model

Liu

Miao

et al. 2023

Front. Endocrinol.

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IntroductionGnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare autosomal dominant disorder characterized by diaphyseal sclerosis of tubular bones and cemento-osseous lesions in mandibles. GDD is caused by point mutations in the ANO5 gene. However, the mechanisms underlying GDD have not been disclosed. We previously generated the first knock-in mouse model for GDD expressing a human mutation (p.Cys360Tyr) in ANO5 and homozygous Ano5 knock-in (Ano5KI/KI) mice exhibited representative traits of human GDD especially including enhanced osteogenesis.MethodsMetabolomics and transcriptomics analyses were conducted for wildtype (Ano5+/+) and Ano5KI/KI mature mouse calvarial osteoblasts (mCOBs) grown in osteogenic cultures for 14 days to identify differential intracellular metabolites and genes involved in GDD. Subsequently, related differential genes were validated by qRT-PCR. Cell proliferation was confirmed by CCK8 assay and calcium content in mineral nodules was detected using SEM-EDS.ResultsMetabolomics identified 42 differential metabolites that are primarily involved in amino acid and pyrimidine metabolism, and endocrine and other factor-regulated calcium reabsorption. Concomitantly, transcriptomic analysis revealed 407 differentially expressed genes in Ano5KI/KI osteoblasts compared with wildtype. Gene ontology and pathway analysis indicated that Ano5Cys360Tyr mutation considerably promoted cell cycle progression and perturbed calcium signaling pathway, which were confirmed by validated experiments. qRT-PCR and CCK-8 assays manifested that proliferation of Ano5KI/KI mCOBs was enhanced and the expression of cell cycle regulating genes (Mki67, Ccnb1, and Ccna2) was increased. In addition, SEM-EDS demonstrated that Ano5KI/KI mCOBs developed higher calcium contents in mineral nodules than Ano5+/+ mCOBs, while some calcium-related genes (Cacna1, Slc8a1, and Cyp27b1) were significantly up-regulated. Furthermore, osteocalcin which has been proved to be an osteoblast-derived metabolic hormone was upregulated in Ano5KI/KI osteoblast cultures.DiscussionOur data demonstrated that the Ano5Cys360Tyr mutation could affect the metabolism of osteoblasts, leading to unwonted calcium homeostasis and cellular proliferation that can contribute to the underlying pathogenesis of GDD disorders.

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“…GDD has been first described by Akasaka et al ( 1969 ) in a Japanese pedigree, but to date, other families of Italian, American, Asian Indians, Caucasian, and Chinese, as well as sporadic case reports have been documented (Duong et al, 2016 ; Marconi et al, 2013 ; Rolvien et al, 2017 , Sandal et al, 2021 ; Tsunami et al, 2003 , 2004 ). Tsunami et al ( 2003 , 2004 ) showed that mutations in anoctamin 5 (ANO5 ; OMIM #608662 ) gene are responsible for the molecular cause of GDD, which is a protein‐coding gene within the GDD critical region on 11p15.1‐p14.3.…”

Section: Introductionmentioning

confidence: 99%

Gnathodiaphyseal dysplasia with a novel genetic variant in a large family from Iran

Yassaee

Khojasteh

Hashemi‐Gorji

et al. 2022

Molec Gen & Gen Med

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ANO5‐associated Gnathodiaphyseal dysplasia with calvarial doughnut lesions: First report in an Asian Indian with an expanded phenotype

Cited by 4 publications

References 6 publications

Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia

Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia

Integration of metabolomics and transcriptomics provides insights into enhanced osteogenesis in Ano5Cys360Tyr knock-in mouse model

Gnathodiaphyseal dysplasia with a novel genetic variant in a large family from Iran

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