Expression of the Type I Diabetes-associated Gene LRP5 in Macrophages, Vitamin A System Cells, and the Islets of Langerhans Suggests Multiple Potential Roles in Diabetes

Figueroa, David J.; Hess, J. Fred; Ky, Betty; Brown, S. D.; Sandig, Volker; Hermanowski‐Vosatka, Anne; Twells, Rebecca C.J.; Todd, John A.; Austin, Christopher P.

doi:10.1177/002215540004801006

Cited by 57 publications

(47 citation statements)

References 34 publications

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“…18 In addition, there is abundant LRP5 expression in convoluted tubules of human and mouse kidneys. 19 Canonical Wnt signaling is established by binding of a Wnt ligand to a cognate Frizzled receptor in the presence of LRP5. The role of canonical Wnt signaling in ADPKD has been an area of research.…”

Section: Discussionmentioning

confidence: 99%

LRP5 variants may contribute to ADPKD

et al. 2015

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Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD). Here, we demonstrate that this gene may also have a role in unlinked and sporadic ADPKD patients. In a cohort of 79 unrelated patients with adult-onset ADPKD, we identified a total of four different LRP5 variants that were predicted to be pathogenic by in silico tools. One ADPKD patient has a positive family history for ADPKD and variant LRP5 c.1680G4T; p.(Trp560Cys) segregated with the disease. Although also two PKD1 variants probably affecting protein function were identified, luciferase activity assays presented for three LRP5 variants significant decreased signal activation of canonical Wnt signaling. This study contributes to the genetic spectrum of ADPKD. Introduction of the canonical Wnt signaling pathway provides new avenues for the study of the pathophysiology.

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Section: Discussionmentioning

confidence: 99%

LRP5 variants may contribute to ADPKD

et al. 2015

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“…In situ hybridization was carried out using an anti-fluorescein horseradish peroxidase conjugate (NEN Life Sciences) in combination with the TSA-Direct kit (NEN Life Sciences). Immunohistochemistry was carried out sequentially after in situ signal development, as described (21). Antibodies for tyrosine hydroxylase (Chemicon), Protein Gene Product 9.5 (Biomeda Corporation, Foster City, CA), nitric oxide synthase (Sigma), choline acetyltransferase (Chemicon), neurofilament protein (DAKO), and smooth muscle actin (DAKO) were used at the manufacturer's specified dilutions and incubated with sections for 2 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A role for the melanocortin 4 receptor in sexual function

Ploeg

Martin

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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281

207

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By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective nonpeptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.O ur understanding of the physiology and anatomy of erectile function has advanced considerably in recent years (1-4). Penile erection is a highly coordinated reflex that is subject to modulation at many levels of the neuraxis. Relaxation of smooth muscle fibers of erectile tissue and concomitant dilatation of the arterial supply in the penis produce penile erection. Activation of neurons in the sacral spinal cord triggers activity in the pelvic nerve and, subsequently, the cavernous nerve, which can lead to the release of mediators of vasorelaxation, including nitric oxide. These mediators modulate cyclic nucleotide levels resulting in Ca 2ϩ sequestration and relaxation of smooth muscle fibers of the corpora cavernosa and corpus spongiosum in the shaft of the penis to produce arterial dilatation, engorgement of the penis with blood, and tumescence. Erections can be triggered either by peripheral (tactile) or by central (visual, olfactory, auditory, or imaginative cues) activation of somatic pathways and, as such, are influenced by tonic and phasic activity in the lumbosacral spinal cord and the brain.Five melanocortin heterotrimeric GTP-binding protein (G protein)-coupled receptors have been identified as expressed in different tissues (5, 6). The functional role of each of these five melanocortin receptors is being defined. Rodent and human genetic and pharmacological evidence indicates that activation of melanocortin 4 receptor (MC4R) results in a lean phenotype, whereas inactivation of the MC4R results in obesity (7-10). Recent studies have demonstrated that MTII, a cyclic analogue of ␣-mel...

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“…Polymorphisms in the promoter region of the LRP5 gene have been associated with type 1A diabetes. LRP5 is a member of the low-density lipoprotein receptor family that is expressed in cells of the mononuclear-phagocyte system, the islets of Langerhans, vitamin A-metabolising cells, and CNS neurons [131]. Vitamin D receptor polymorphisms have been associated with risk for type 1A diabetes in several populations [132,133,134,135].…”

Section: Other Genes and Locimentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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Expression of the Type I Diabetes-associated Gene LRP5 in Macrophages, Vitamin A System Cells, and the Islets of Langerhans Suggests Multiple Potential Roles in Diabetes

Cited by 57 publications

References 34 publications

LRP5 variants may contribute to ADPKD

LRP5 variants may contribute to ADPKD

A role for the melanocortin 4 receptor in sexual function

Genetic control of autoimmunity in Type I diabetes and associated disorders

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