A role for the <i>MEGF6</i> gene in predisposition to osteoporosis

Teerlink, Craig C.; Jurynec, Michael J.; Hernandez, Rolando; Stevens, Jeff; Hughes, Dana; Brunker, Cherie; Rowe, Kerry; Grunwald, David J.; Facelli, Julio C.; Cannon-Albright, Lisa

doi:10.1111/ahg.12408

Cited by 18 publications

(13 citation statements)

References 66 publications

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“…Sturnickel et al [5] found 25 individuals with LRP5 allelic variants and 6 with LRP6 variants among 371 patients with early-onset osteoporosis, but none of the LRP6 variants were classified as damaging. However, no LRP6 mutations were found in other studies of osteoporosis in young people or among some familiar cases of osteoporosis [11][12][13][14]. Interestingly, recent reports show that, similarly to gain-of-function mutations of LRP5, some LRP6 activating mutations may result in generalized high bone mass or localized bone sclerosis [15,16].…”

Section: Discussionmentioning

confidence: 98%

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

et al. 2022

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We present a family with a rare mutation of the LRP6 gene and for the first time provide evidence for its association with low bone mineral density. Introduction The Wnt pathway plays a critical role in bone homeostasis. Pathogenic variants of the Wnt co-receptor LRP6 have been associated with abnormal skeletal phenotypes or increased risk of cardiovascular events. Patient and methods Here we report an index premenopausal patient and her family carrying a rare missense LRP6 pathogenic variant (rs141212743; 0.0002 frequency among Europeans). This variant has been previously associated with metabolic syndrome and atherosclerosis, in the presence of normal bone mineral density. However, the LRP6 variant was associated with low bone mineral density in this family, without evidence for association with serum lipid levels or cardiovascular events. Conclusion Thus, this novel association shows that LRP6 pathogenic variants may be involved in some cases of early-onset osteoporosis, but the predominant effect, either skeletal or cardiovascular, may vary depending on the genetic background or other acquired factors.

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Section: Discussionmentioning

confidence: 98%

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

et al. 2022

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“…In the post-natal hypoxia group, genes that were highly differentially expressed in comparison to the control group included functions such as regulation of cellular cholesterol metabolism (Pip4p1; Phosphatidylinositol-4,5-Bisphosphate 4-Phosphatase 1) (Hammond & Burke, 2020), calcium ion binding activity (Megf6; Multiple Epidermal Growth Factor-Like Domains Protein 6) (Teerlink et al, 2021), regulation of cell growth in differentiating tissues (Mxd4; MAX Dimerization Protein 4) (Boros et al, 2011), and axon guidance during neuronal development (Sema3f; Semaphorin 3F). Interestingly, Slc26a3, Cyp3a13, Megf6, and Trpv4 were all among the top most differentially-expressed genes for both lifelong and post-natal hypoxia exposures.…”

Section: What Are the Underlying Gene Regulatory Changes That Contrib...mentioning

confidence: 99%

Gene regulatory changes underlie developmental plasticity in respiration and aerobic performance in highland deer mice

Schweizer

Ivy

Natarajan

et al. 2022

Preprint

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Phenotypic plasticity can play an important role in the ability of animals to tolerate environmental stress, but the nature and magnitude of plastic responses are often specific to the developmental timing of exposure. Here, we examine changes in gene expression in the diaphragm of highland deer mice (Peromyscus maniculatus) in response to hypoxia exposure at different stages of development. In highland deer mice, developmental plasticity in diaphragm function may mediate changes in several respiratory traits that influence aerobic metabolism and performance under hypoxia. We generated RNAseq data from diaphragm tissue of adult deer mice exposed to 1) life-long hypoxia (before conception to adulthood), 2) post-natal hypoxia (birth to adulthood), 3) adult hypoxia (6-8 weeks only during adulthood), or 4) normoxia. We found five suites of co-regulated genes that are differentially expressed in response to hypoxia, but the patterns of differential expression depend on the developmental timing of exposure. We also identified four transcriptional modules that are associated with important respiratory traits. Many of the genes in these transcriptional modules bear signatures of altitude-related selection, providing an indirect line of evidence that observed changes in gene expression may be adaptive in hypoxic environments. Our results demonstrate the importance of developmental stage in determining the phenotypic response to environmental stressors.

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“…Following our previous approaches to demonstrate the usefulness of protein prediction methods to elucidate pathogenicity [10,[20][21][22][23], the canonical/reference sequence for the ERF protein was retrieved from UniProt (Uniprot ID: P50548) [24]. The variant sequence was manually modified and the two resulting sequences were submitted to the Phyre2 server [25] on intensive mode for structure prediction.…”

Section: Protein Prediction Modelingmentioning

confidence: 99%

A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree

Cannon‐Albright

Teerlink

Stevens

et al. 2021

Cancers

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Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for segregation to other related cancer cases, and the predicted protein structure of this variant was analyzed. This study of affected bladder cancer relative pairs from high-risk pedigrees identified 152 bladder cancer predisposition candidate variants. One variant in ERF (ETS Repressing Factor) was significantly associated with bladder cancer risk in an independent population, was observed to segregate with bladder and prostate cancer in relatives, and showed evidence for altering the function of the associated protein. This finding of a rare variant in ERF that is strongly associated with bladder and prostate cancer risk in an extended pedigree both validates ERF as a cancer predisposition gene and shows the continuing value of analyzing affected members of high-risk pedigrees to identify and validate rare cancer predisposition variants.

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A role for the MEGF6 gene in predisposition to osteoporosis

Cited by 18 publications

References 66 publications

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family

Gene regulatory changes underlie developmental plasticity in respiration and aerobic performance in highland deer mice

A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree

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