Pre-B lymphocyte protein 3 (VPREB3) expression in the adrenal cortex: precedent for non-immunological roles in normal and neoplastic human tissues
Abstract
The pre-B lymphocyte protein 3 (VPREB3) is expressed during B cell differentiation and in subsets of mature B lymphocytes and is mainly found in bone marrow and lymphoid tissue germinative centers. So far, its function in B cells remains to be clarified. The messenger RNA (mRNA) of VPREB3 was previously detected in aldosterone-producing adenomas (APA); however, further information about this protein in human adrenocortical cells and tissues is currently unavailable. Therefore, in the present study, we, for the first time, investigate the protein expression of VPREB3 in human adrenocortical tissues. In addition, we approach the previously suggested similarities in expression patterns of aldosterone-producing cells and Purkinje neurons. Immunohistochemical analysis of VPREB3 was performed in 13 nonpathological adrenals (NA), 6 adrenal glands with idiopathic hyperaldosteronism (IHA), 18 APA, 5 cortisol-producing adenomas (CPA), and 5 nonpathological human cerebellum specimens. The mRNA levels of VPREB3, steroidogenic enzymes, and other aldosterone biosynthesis markers were detected in 53 APA samples using real-time RT-PCR (qPCR) and compared to the clinical data of APA patients. In our results, the VPREB3 protein was diffusely detected in APA, partially or weakly detected in CPA, and immunolocalized in the zona glomerulosa of NA and IHA, as well as in the cytoplasm of cerebellar Purkinje cells. In APA, VPREB3 mRNA levels were significantly correlated to plasma aldosterone (P = 0.026; R = 0.30), KCNJ5 mutations (P = 0.0061; mutated 34:19 wild type), CYP11B2 (P < 0.0001; R = 0.65), Purkinje cell protein 4 (PCP4; P < 0.0001; R = 0.53), and voltage-dependent calcium channels CaV1.3 (P = 0.023; R = 0.31) and CaV3.2 (P = 0.0019; R = 0.42). Based on our data, we hypothesize a possible role for VPREB3 in aldosterone biosynthesis, and present ideas for future functional studies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
KCNJ5 mutations have been documented in approximately 40% of patients with aldosterone-producing adenomas from European cohorts, with much higher rates reported in patients from Japan and Asia.
“Mutations in KCNJ5 (potassium channel) have been documented in patients with aldosterone-producing adenomas in approximately 40% of patients (151) from European cohorts, though much higher rates are reported in patients from Japan and Asia (152,153).”
From Adrenal incidentaloma (2020) · cites this paper as [153]
Cites
B lymphocytes: how they develop and function
LeBien, T. W., & Tedder, T. F. (2008) · Blood · doi:10.1182/blood-2008-02-078071 · Cited by 1,400 · see citing works
Molecular and Cellular Endocrinology
Rainey, W. E., & Rodgers, R. J. (2004) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2004.10.007 · Cited by 1,309 · see citing works
K + Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension
Choi, M., Scholl, U. I., Yue, P., Björklund, P., Zhao, B., Nelson-Williams, C. J., Ji, W., Cho, Y., Patel, A. P., Men, C. J., et al. (2011) · Science · doi:10.1126/science.1198785 · Cited by 999 · see citing works
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension
Azizan, E. A. B., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M. V., Lieb, A., Maniero, C., Garg, S., Bochukova, E. G., Zhao, W., et al. (2013) · Nature Genetics · doi:10.1038/ng.2716 · Cited by 544 · see citing works
Doi, M., Takahashi, Y., Komatsu, R., Yamazaki, F., Yamada, H., Haraguchi, S., Emoto, N., Okuno, Y., Tsujimoto, G., Kanematsu, A., et al. (2010) · Nature Medicine · doi:10.1038/nm.2061 · Cited by 431 · see citing works
Ganor, Y., Besser, M. J., Ben-Zakay, N., Unger, T., & Levite, M. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.8.4362 · Cited by 188 · see citing works
Glynne, R., Ghandour, G., Rayner, J. R., et al. (2000) · Immunological Reviews · doi:10.1034/j.1600-065x.2000.00614.x · Cited by 183 · see citing works
Sukor, N., Gordon, R. D., Ku, Y. K., Jones, M., & Stowasser, M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2803 · Cited by 164 · see citing works
Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree
Vawter, M. P. (2003) · Schizophrenia Research · doi:10.1016/s0920-9964(03)00151-8 · Cited by 132 · see citing works
Expression of 11beta-hydroxylase and aldosterone synthase genes in the rat brain
MacKenzie, S. M., CLARK, C. J., Fräser, R., Gómez-Sánchez, C. E., Connell, J. M. C., & Davies, E. (2000) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0240321 · Cited by 124 · see citing works
Satoh, F., Abe, T., Tanemoto, M., Nakamura, M., Abe, M., Uruno, A., Morimoto, R., Akihiro, S. A. T. O., Takase, K., Ishidoya, S., et al. (2007) · Hypertension Research · doi:10.1291/hypres.30.1083 · Cited by 112 · see citing works
Self-citationZona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators
Hu, C., Rusin, C. G., Tan, Z., Guagliardo, N. A., & Barrett, P. Q. (2012) · Journal of Clinical Investigation · doi:10.1172/jci61996 · Cited by 105 · see citing works
Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans
Hills, L. B., Masri, A. T., Konno, K., Kakegawa, W., Lam, A.-T. N., Lim-Melia, E. R., Chandy, N., Hill, R. S., Partlow, J. N., Al‐Saffar, M., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a841a3 · Cited by 101 · see citing works
Lurcher GRID2-Induced Death and Depolarization Can Be Dissociated in Cerebellar Purkinje Cells
Selimi, F., Lohof, A. M., Heitz, S., Lalouette, A., Jarvis, C. I., Bailly, Y. J. R., & Mariani, J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00093-x · Cited by 78 · see citing works
Nakamura, Y., Satoh, F., Morimoto, R., Kudo, M., Takase, K., Gómez-Sánchez, C. E., Honma, S., Okuyama, M., Yamashita, K., Rainey, W. E., et al. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2785 · Cited by 78 · see citing works
Self-citationA Homozygous Deletion in GRID2 Causes a Human Phenotype With Cerebellar Ataxia and Atrophy
Ütine, G. E., Haliloğlu, G., Salancı, B. V., Çetinkaya, A., Şimşek‐Kiper, P. Ö., Alanay, Y., Aktaş, D., Boduroğlu, K., & Alikaşifoğlu, M. (2013) · Journal of Child Neurology · doi:10.1177/0883073813484967 · Cited by 72 · see citing works
Nogueira, E. F., Vargas, C. A., Otis, M., Gallo‐Payet, N., Bollag, W. B., & Rainey, W. E. (2007) · Journal of Molecular Endocrinology · doi:10.1677/jme-07-0094 · Cited by 68 · see citing works
Impaired Locomotor Learning and Altered Cerebellar Synaptic Plasticity in pep-19/pcp4-Null Mice
Peng, W., Blundon, J. A., Rong, Y., Zakharenko, S. S., & Morgan, J. I. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05208-11 · Cited by 68 · see citing works
Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands
Wang, T., Satoh, F., Morimoto, R., Nakamura, Y., Sasano, H., Auchus, R. J., Edwards, M. A., & Rainey, W. E. (2011) · European Journal of Endocrinology · doi:10.1530/eje-10-1085 · Cited by 63 · see citing works
Self-citationDoi, M., Satoh, F., Maekawa, T., Nakamura, Y., Fustin, J., Tainaka, M., Hotta, Y., Takahashi, Y., Morimoto, R., Takase, K., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3279 · Cited by 55 · see citing works
Self-citationSchil, K. V., Meire, F. M., Karlstetter, M., Bauwens, M., Verdin, H., Coppieters, F., Scheiffert, E., Nechel, C. V., Langmann, T., Deconinck, N., et al. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.95 · Cited by 44 · see citing works
3β-hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma
Konosu‐Fukaya, S., Nakamura, Y., Satoh, F., Felizola, S. J. A., Maekawa, T., Ono, Y., Morimoto, R., Ise, K., Takeda, K.-I., Katsu, K., et al. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.10.008 · Cited by 43 · see citing works
Self-citationVoltage-gated calcium channels in the human adrenal and primary aldosteronism
Felizola, S. J. A., Maekawa, T., Nakamura, Y., Satoh, F., Ono, Y., Kikuchi, K., Aritomi, S., Ikeda, K., Yoshimura, M., Tojo, K., et al. (2014) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.08.012 · Cited by 40 · see citing works
Self-citationKakegawa, W., Miyazaki, T., Hirai, H., Motohashi, J., Mishina, M., Watanabe, M., & Yuzaki, M. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2006.127100 · Cited by 38 · see citing works
Rodig, S. J., Kutok, J. L., Paterson, J. C., et al. (2010) · Haematologica · doi:10.3324/haematol.2010.025767 · Cited by 37 · see citing works
Rosnet, O., Blanco-Betancourt, C., Grivel, K., Richter, K., & Schiff, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312169-a200 · Cited by 34 · see citing works
PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues
Felizola, S. J. A., Nakamura, Y., Ono, Y., Kitamura, K., Kikuchi, K., Onodera, Y., Ise, K., Takase, K., Sugawara, A., Hattangady, N. G., et al. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0248 · Cited by 31 · see citing works
Self-citationFelizola, S. J. A., Nakamura, Y., Satoh, F., Morimoto, R., Kikuchi, K., Nakamura, T., Hozawa, A., Wang, L., Onodera, Y., Ise, K., et al. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.09.025 · Cited by 30 · see citing works
Self-citationMetallothionein-3 (MT-3) in the Human Adrenal Cortex and its Disorders
Felizola, S. J. A., Nakamura, Y., Arata, Y., Ise, K., Satoh, F., Rainey, W. E., Midorikawa, S., Suzuki, S., & Sasano, H. (2013) · Endocrine Pathology · doi:10.1007/s12022-013-9280-9 · Cited by 30 · see citing works
Self-citationDissecting the molecular pathways of primary aldosteronism
Nakamura, Y., Felizola, S. J. A., Satoh, F., Konosu‐Fukaya, S., & Sasano, H. (2014) · Pathology International · doi:10.1111/pin.12200 · Cited by 21 · see citing works
Self-citationVPREB3: cDNA characterization and expression in human and chromosome mapping in human and mouse
Rosnet, O., Mattéi, M., Delattre, O., et al. (1999) · Cytogenetic and Genome Research · doi:10.1159/000015468 · Cited by 20 · see citing works
Mutations in KCNJ5 Gene Cause Hyperaldosteronism
Zennaro, M., & Jeunemaı̂tre, X. (2011) · Circulation Research · doi:10.1161/res.0b013e318224a359 · Cited by 18 · see citing works
Breese, C. R., Logel, J., Adams, C. E., & Leonard, S. S. (1996) · Journal of Molecular Neuroscience · doi:10.1007/bf02737065 · Cited by 15 · see citing works
A VpreB3 homologue in a marsupial, the gray short-tailed opossum, Monodelphis domestica
Wang, X., Parra, Z. E., & Miller, R. D. (2012) · Immunogenetics · doi:10.1007/s00251-012-0626-0 · Cited by 14 · see citing works
Bouillet, P., Robati, M., Adams, J. M., & Strasser, A. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10805 · Cited by 9 · see citing works
Morphology of Adrenal Gland and Lymph Organs is Impaired in Neurodeficient Lurcher Mutant Mice
Beranová, M., Manďáková, P., Šíma, P., et al. (2002) · Acta Veterinaria Brno · doi:10.2754/avb200271010023 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sherlock, M., Scarsbrook, A., Abbas, A., Fraser, S., Limumpornpetch, P., Dineen, R., & Stewart, P. M. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa008 · Cited by 347 · see citing works
“Mutations in KCNJ5 , CACNA1H , ATP1A1 , ATP2B3 , and CACNA1D account for approximately 50% of aldosterone-producing adrenal adenomas (159) in patients from Europe; this is likely to be higher in Asian patients.”
Background
- Authors
- Felizola, S. J. A., Katsu, K., Ise, K., Nakamura, Y., Arai, Y., Satoh, F., & Sasano, H.
- Affiliations
- Tohoku University (JP)
- Tohoku University Hospital (JP)
- Corresponding author
- Felizola, Saulo J. A.
- Venue
- Endocrine Pathology
- Published
- 2015-04-10
- Volume
- 26
- Issue
- 2
- Pages
- 119-128
- ISSN
- 1046-3976 (ISSN-L)
- 1559-0097
- OpenAlex
- W1991812866
- Cited by
- 15
- References
- 36
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 1 · 2017: 2 · 2016: 1
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Endocrine Pathology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- adrenal cortex, aldosterone-producing adenoma, idiopathic hyperaldosteronism, cortisol-producing adenoma, Purkinje cells, KCNJ5 mutation, CYP11B2, voltage-gated calcium channels, Cav1.3, Cav3.2, B cell differentiation
- MeSH terms
- Adenoma, Adrenal Cortex, Adrenal Cortex Neoplasms, Aldosterone, Angiotensin II, Humans, Mutation, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Metabolic Networks and Pathways, Pre-B Cell Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review