Copy number variation of the APC gene is associated with regulation of bone mineral density

Chew, Shelby; Dastani, Zari; Brown, Suzanne J.; Lewis, Joshua R.; Dudbridge, Frank; Soranzo, Nicole; Surdulescu, Gabriela L.; Richards, J. Brent; Spector, Tim D.; Wilson, Scott G.

doi:10.1016/j.bone.2012.07.022

Cited by 15 publications

(9 citation statements)

References 41 publications

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“…A few other examples in humans of SVs operating to modulate metabolic activities have also emerged. One study was able to calculate that Caucasian individuals with a single copy loss of the tumor suppressor APC locus had a net increase in bone mineral density of the forearm ($8%), spine (13%) and hip (13%) [52]. In a study of men from Sweden and Korea, urinary testosterone concentrations were shown to correlate with UGT2B17 allele count.…”

Section: Metabolic Processesmentioning

confidence: 99%

Adaptive potential of genomic structural variation in human and mammalian evolution

Radke¹,

Lee²

2015

Briefings in Functional Genomics

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Because phenotypic innovations must be genetically heritable for biological evolution to proceed, it is natural to consider new mutation events as well as standing genetic variation as sources for their birth. Previous research has identified a number of single-nucleotide polymorphisms that underlie a subset of adaptive traits in organisms. However, another well-known class of variation, genomic structural variation, could have even greater potential to produce adaptive phenotypes, due to the variety of possible types of alterations (deletions, insertions, duplications, among others) at different genomic positions and with variable lengths. It is from these dramatic genomic alterations, and selection on their phenotypic consequences, that adaptations leading to biological diversification could be derived. In this review, using studies in humans and other mammals, we highlight examples of how phenotypic variation from structural variants might become adaptive in populations and potentially enable biological diversification. Phenotypic change arising from structural variants will be described according to their immediate effect on organismal metabolic processes, immunological response and physical features. Study of population dynamics of segregating structural variation can therefore provide a window into understanding current and historical biological diversification.

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Section: Metabolic Processesmentioning

confidence: 99%

Adaptive potential of genomic structural variation in human and mammalian evolution

Radke¹,

Lee²

2015

Briefings in Functional Genomics

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“…In this study, we focused on rare damaging single-nucleotide variants. Copy number variants (CNVs) can also influence the risk of many diseases and are associated with several skeletal phenotypes 41–43. In one study, more than 6% of patients with AIS were found to harbour a clinically important copy number abnormality, and some of these abnormalities may play a role in AIS pathogenesis 44.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing analysis identifies frequent oligogenic involvement andFLNBvariants in adolescent idiopathic scoliosis

Jiang

Liang

et al. 2020

J Med Genet

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BackgroundAdolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait.ObjectiveWe aimed to explore the oligogenic nature of this disease and identify novel AIS genes.MethodsWe analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients.ResultsMultiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein’s conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis.ConclusionOur data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.

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“…Although variations in bone mass are not a clinical hallmark of Familial Adenomatous Polyposis (FAP), two studies have shown a direct association between the presence of an APC mutation and BMD values in humans [22,23]. A cross-sectional study on 30 FAP patients bearing a germinal heterozygote mutation of the APC gene showed a significantly higher mean BMD at the lumbar spine, total hip, femoral neck and trochanter in FAP patients, with respect to age-and gender-matched healthy controls, in the presence of a balanced bone remodeling, as displayed by the mean concentrations of procollagen type I N-terminal propeptide and β-crosslaps being within the normal ranges [22].…”

Section: Apc Genementioning

confidence: 99%

Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

Marini

Giusti

Iantomasi

et al. 2021

Genes

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Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients.

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Copy number variation of the APC gene is associated with regulation of bone mineral density

Cited by 15 publications

References 41 publications

Adaptive potential of genomic structural variation in human and mammalian evolution

Adaptive potential of genomic structural variation in human and mammalian evolution

Exome sequencing analysis identifies frequent oligogenic involvement andFLNBvariants in adolescent idiopathic scoliosis

Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

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