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2. GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification

Author

Knöpfel, Nicole, Zecchin, Davide, Richardson, Hanna, Polubothu, Satyamaanasa, Barberan-Martin, Sara, Cullup, Thomas, Gholam, Karolina, Heales, Simon, Krywawych, Steve, López-Balboa, Pablo, Muwanga-Nanyonjo, Noreen, Ogunbiyi, Olumide, Puvirajasinghe, Clinda, Solman, Lea, Swarbrick, Katherine, Syed, Samira B., Tahir, Zubair, Tisdall, Martin M., Allgrove, Jeremy, Chesover, Alexander D., Aylett, Sarah E., Jacques, Thomas S., Hannan, Fadil M., Löbel, Ulrike, Semple, Robert K., Thakker, Rajesh V., and Kinsler, Veronica A.

Published
2024
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4. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Pagnamenta, Alistair T., Camps, Carme, Giacopuzzi, Edoardo, Taylor, John M., Hashim, Mona, Calpena, Eduardo, Kaisaki, Pamela J., Hashimoto, Akiko, Yu, Jing, Sanders, Edward, Schwessinger, Ron, Hughes, Jim R., Lunter, Gerton, Dreau, Helene, Ferla, Matteo, Lange, Lukas, Kesim, Yesim, Ragoussis, Vassilis, Vavoulis, Dimitrios V., Allroggen, Holger, Ansorge, Olaf, Babbs, Christian, Banka, Siddharth, Baños-Piñero, Benito, Beeson, David, Ben-Ami, Tal, Bennett, David L., Bento, Celeste, Blair, Edward, Brasch-Andersen, Charlotte, Bull, Katherine R., Cario, Holger, Cilliers, Deirdre, Conti, Valerio, Davies, E. Graham, Dhalla, Fatima, Dacal, Beatriz Diez, Dong, Yin, Dunford, James E., Guerrini, Renzo, Harris, Adrian L., Hartley, Jane, Hollander, Georg, Javaid, Kassim, Kane, Maureen, Kelly, Deirdre, Kelly, Dominic, Knight, Samantha J. L., Kreins, Alexandra Y., Kvikstad, Erika M., Langman, Craig B., Lester, Tracy, Lines, Kate E., Lord, Simon R., Lu, Xin, Mansour, Sahar, Manzur, Adnan, Maroofian, Reza, Marsden, Brian, Mason, Joanne, McGowan, Simon J., Mei, Davide, Mlcochova, Hana, Murakami, Yoshiko, Németh, Andrea H., Okoli, Steven, Ormondroyd, Elizabeth, Ousager, Lilian Bomme, Palace, Jacqueline, Patel, Smita Y., Pentony, Melissa M., Pugh, Chris, Rad, Aboulfazl, Ramesh, Archana, Riva, Simone G., Roberts, Irene, Roy, Noémi, Salminen, Outi, Schilling, Kyleen D., Scott, Caroline, Sen, Arjune, Smith, Conrad, Stevenson, Mark, Thakker, Rajesh V., Twigg, Stephen R. F., Uhlig, Holm H., van Wijk, Richard, Vona, Barbara, Wall, Steven, Wang, Jing, Watkins, Hugh, Zak, Jaroslav, Schuh, Anna H., Kini, Usha, Wilkie, Andrew O. M., Popitsch, Niko, and Taylor, Jenny C.

Published
2023
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9. Skeletal and extraskeletal disorders of biomineralization

Author

Collins, Michael T., Marcucci, Gemma, Anders, Hans-Joachim, Beltrami, Giovanni, Cauley, Jane A., Ebeling, Peter R., Kumar, Rajiv, Linglart, Agnès, Sangiorgi, Luca, Towler, Dwight A., Weston, Ria, Whyte, Michael. P., Brandi, Maria Luisa, Clarke, Bart, and Thakker, Rajesh V.

Published
2022
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11. Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes

Author

Shariq, Omair A., Lines, Kate E., English, Katherine A., Jafar-Mohammadi, Bahram, Prentice, Philippa, Casey, Ruth, Challis, Benjamin G., Selberherr, Andreas, Boon, Hannah, Cranston, Treena, Ryan, Fiona J., Mihai, Radu, Healy, Ultan, Kurzawinski, Tom, Dattani, Mehul T., Bancos, Irina, Dy, Benzon M., Lyden, Melanie L., Young, William F., Jr., McKenzie, Travis J., Richards, Duncan, and Thakker, Rajesh V.

Published
2022
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12. Identification of cellular retinoic acid binding protein 2 (CRABP2) as downstream target of nuclear factor I/X (NFIX): implications for skeletal dysplasia syndromes.

Author

Kooblall, Kreepa G, Stevenson, Mark, Heilig, Raphael, Stewart, Michelle, Wright, Benjamin, Lockstone, Helen, Buck, David, Fischer, Roman, Wells, Sara, Lines, Kate E, Teboul, Lydia, Hennekam, Raoul C, and Thakker, Rajesh V

Subjects
GLIAL fibrillary acidic protein, CELL adhesion molecules, REVERSE transcriptase polymerase chain reaction, TRANSCRIPTION factors, GENE expression, DYSPLASIA
Abstract

Nuclear factor I/X (NFIX) mutations are associated with 2 skeletal dysplasias, Marshall-Smith (MSS) and Malan (MAL) syndromes. NFIX encodes a transcription factor that regulates expression of genes, including Bobby sox (BBX) and glial fibrillary acidic protein (GFAP) in neural progenitor cells and astrocytes, respectively. To elucidate the role of NFIX mutations in MSS, we studied their effects in fibroblast cell lines obtained from 5 MSS unrelated patients and 3 unaffected individuals. The 5 MSS NFIX frameshift mutations in exons 6-8 comprised 3 deletions (c.819-732_1079-948del, c.819-471_1079-687del, c.819-592_1079-808del), an insertion (c.1037_1038insT), and a duplication (c.1090dupG). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses using MSS and unrelated control fibroblasts and in vitro expression studies in monkey kidney fibroblast (COS-7) cells showed that frameshift mutations in NFIX exons 6-8 generated mutant transcripts that were not cleared by nonsense-mediated-decay mechanisms and encoded truncated NFIX proteins. Moreover, BBX or GFAP expression was unaffected in the majority of MSS fibroblasts. To identify novel NFIX downstream target genes, RNA sequencing and proteomics analyses were performed on mouse embryonic fibroblast (MEF) cells derived from control Nfix+/+ , Nfix+/Del2 , Nfix+/Del24, NfixDel24/Del24 , Nfix+/Del140 , and NfixDel140/Del140 mice, compared with NfixDel2/Del2 mice which had developmental, skeletal, and neural abnormalities. This identified 191 transcripts and 815 proteins misregulated in NfixDel2/Del2 MEFs with ≥2-fold-change (P  <0 .05). Validation studies using qRT-PCR and western blot analyses confirmed that 2 genes, cellular retinoic acid binding protein 2 (Crabp2) and vascular cell adhesion molecule 1 (Vcam1), were misregulated at the RNA and protein levels in NfixDel2/Del2 MEFs, and that CRABP2 and VCAM1 expressions were altered in 60%–100% of MSS fibroblast cells. Furthermore, in vitro luciferase reporter assays confirmed that NFIX directly regulates CRABP2 promoter activity. Thus, these altered genes and pathways may represent possible targets for drugs as potential treatments and therapies for MSS. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Asymmetric activation of the calcium-sensing receptor homodimer

Author

Gao, Yang, Robertson, Michael J., Rahman, Sabrina N., Seven, Alpay B., Zhang, Chensong, Meyerowitz, Justin G., Panova, Ouliana, Hannan, Fadil M., Thakker, Rajesh V., Brauner-Osborne, Mathiesen, Jesper M., and Skiniotis, Georgios

Subjects
Calcium, Dietary -- Physiological aspects, Cell receptors -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca.sup.2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders.sup.1. CaSR is a family C G-protein-coupled receptor.sup.2 that functions as an obligate homodimer, with each protomer composed of a Ca.sup.2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca.sup.2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor. Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that is stabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling., Author(s): Yang Gao [sup.1] [sup.2] , Michael J. Robertson [sup.1] [sup.2] , Sabrina N. Rahman [sup.4] , Alpay B. Seven [sup.1] [sup.2] , Chensong Zhang [sup.1] [sup.2] , Justin G. [...]

Published
2021
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16. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

Author

Zhou, Junhua, Azizan, Elena A. B., Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Argentesi, Giulia, Cottrell, Emily, Amar, Laurence, Wu, Xilin, O’Toole, Sam, Goodchild, Emily, Marker, Alison, Senanayake, Russell, Garg, Sumedha, Åkerström, Tobias, Backman, Samuel, Jordan, Suzanne, Polubothu, Satyamaanasa, Berney, Daniel M., Gluck, Anna, Lines, Kate E., Thakker, Rajesh V., Tuthill, Antoinette, Joyce, Caroline, Kaski, Juan Pablo, Karet Frankl, Fiona E., Metherell, Lou A., Teo, Ada E. D., Gurnell, Mark, Parvanta, Laila, Drake, William M., Wozniak, Eva, Klinzing, David, Kuan, Jyn Ling, Tiang, Zenia, Gomez Sanchez, Celso E., Hellman, Per, Foo, Roger S. Y., Mein, Charles A., Kinsler, Veronica A., Björklund, Peyman, Storr, Helen L., Zennaro, Maria-Christina, and Brown, Morris J.

Published
2021
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26. Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1.

Author

Cuny, Thomas, Romanet, Pauline, Goldsworthy, Michelle, Guérin, Carole, Wilkin, Marie, Roche, Philippe, Sebag, Frédéric, Summeren, Lynn E van, Stevenson, Mark, Howles, Sarah A, Deharo, Jean-Claude, Thakker, Rajesh V, and Taïeb, David

Subjects
HYPERCALCEMIA, GENETIC mutation, HYPERPARATHYROIDISM
Abstract

Context Familial hypocalciuric hypercalcemia type 1 (FHH-1) defines an autosomal dominant disease, related to mutations in the CASR gene, with mild hypercalcemia in most cases. Cases of FHH-1 with a short QT interval have not been reported to date. Objective Three family members presented with FHH-1 and short QT interval (<360 ms), a condition that could lead to cardiac arrhythmias, and the effects of cinacalcet, an allosteric modulator of the CaSR, in rectifying the abnormal sensitivity of the mutant CaSR and in correcting the short QT interval were determined. Methods CASR mutational analysis was performed by next-generation sequencing and functional consequences of the identified CaSR variant (p.Ile555Thr), and effects of cinacalcet were assessed in HEK293 cells expressing wild-type and variant CaSRs. A cinacalcet test consisting of administration of 30 mg cinacalcet (8 Am) followed by hourly measurement of serum calcium, phosphate, and parathyroid hormone during 8 hours and an electrocardiogram was performed. Results The CaSR variant (p.Ile555Thr) was confirmed in all 3 FHH-1 patients and was shown to be associated with a loss of function that was ameliorated by cinacalcet. Cinacalcet decreased parathyroid hormone by >50% within two hours, and decreases in serum calcium and increases in serum phosphate occurred within 8 hours, with rectification of the QT interval, which remained normal after 3 months of cinacalcet treatment. Conclusion Our results indicate that FHH-1 patients should be assessed for a short QT interval and a cinacalcet test used to select patients who are likely to benefit from this treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Aberrant methylation underlies insulin gene expression in human insulinoma

Author

Karakose, Esra, Wang, Huan, Inabnet, William, Thakker, Rajesh V., Libutti, Steven, Fernandez-Ranvier, Gustavo, Suh, Hyunsuk, Stevenson, Mark, Kinoshita, Yayoi, Donovan, Michael, Antipin, Yevgeniy, Li, Yan, Liu, Xiaoxiao, Jin, Fulai, Wang, Peng, Uzilov, Andrew, Argmann, Carmen, Schadt, Eric E., Stewart, Andrew F., Scott, Donald K., and Lambertini, Luca

Published
2020
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34. Remote Sensing Pansharpening with TV-H−1 Decomposition and PSO-Based Adaptive Weighting Method.

Author

Sangani, Dhara J., Thakker, Rajesh A., Panchal, S. D., and Gogineni, Rajesh

Abstract

In remote sensing, owing to existing sensors’ limitations and the tradeoff between signal-to-noise ratio (SNR) and instantaneous field of view (IFOV), it is difficult to obtain a single image with good spectral and spatial resolution. Pansharpening (PS) is the technique for sharpening multispectral (MS) images by extracting structural and edge information of panchromatic (PAN) image. Multiscale decomposition methods are used for decomposing image in sub-bands but are affected by ringing artifacts, therefore the resultant image seems to be blurred and misregistered. The proposed method overcomes this drawback by decomposing PAN and four band MS image into cartoon and texture components with total variation (TV) Hilbert−1 model. The particle swarm optimization (PSO) algorithm is used for finding the optimum weight for fusing texture and cartoon details of PAN and MS images. The proposed method is practically validated on both full-scale and reduced-scale. Robustness of our proposed approach is tested on different geographical areas such as hilly, urban, and vegetation areas. From the visual analysis and qualitative parameters, the proposed method is proved effective compared with other traditional approaches. [ABSTRACT FROM AUTHOR]

Published
2023
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40. GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.

Author

Howles, Sarah A., Gorvin, Caroline M., Cranston, Treena, Rogers, Angela, Gluck, Anna K., Boon, Hannah, Gibson, Kate, Rahman, Mushtaqur, Root, Allen, Nesbit, M. Andrew, Hannan, Fadil M., and Thakker, Rajesh V.

Abstract

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gainof- function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calciumsensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. [ABSTRACT FROM AUTHOR]

Published
2023
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41. Tumor-induced Osteomalacia: A Comprehensive Review.

Author

Minisola, Salvatore, Fukumoto, Seiji, Xia, Weibo, Corsi, Alessandro, Colangelo, Luciano, Scillitani, Alfredo, Pepe, Jessica, Cipriani, Cristiana, and Thakker, Rajesh V

Subjects
OSTEOMALACIA, PARANEOPLASTIC syndromes, FIBROBLAST growth factors
Abstract

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision. [ABSTRACT FROM AUTHOR]

Published
2023
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44. Hypoparathyroidism

Author

Mannstadt, Michael, Bilezikian, John P., Thakker, Rajesh V., Hannan, Fadil M., Clarke, Bart L., Rejnmark, Lars, Mitchell, Deborah M., Vokes, Tamara J., Winer, Karen K., and Shoback, Dolores M.

Published
2017
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47. Corrigendum to ‘Multiple endocrine neoplasia type 1 in children and adolescents: Clinical features and treatment outcomes’ [Surgery 171 (2021) 77–87]

Author

Shariq, Omair A., Lines, Kate E., English, Katherine A., Jafar-Mohammadi, Bahram, Prentice, Philippa, Casey, Ruth, Challis, Benjamin G., Selberherr, Andreas, Boon, Hannah, Cranston, Treena, Ryan, Fiona J., Mihai, Radu, Healy, Ultan, Kurzawinski, Tom, Dattani, Mehul T., Bancos, Irina, Dy, Benzon M., Lyden, Melanie L., Young, William F., Jr., McKenzie, Travis J., Richards, Duncan, and Thakker, Rajesh V.

Published
2022
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50. Increased Population Risk of AIP‐Related Acromegaly and Gigantism in Ireland

Author

Radian, Serban, Diekmann, Yoan, Gabrovska, Plamena, Holland, Brendan, Bradley, Lisa, Wallace, Helen, Stals, Karen, Bussell, Anna‐Marie, McGurren, Karen, Cuesta, Martin, Ryan, Anthony W., Herincs, Maria, Hernández‐Ramírez, Laura C., Holland, Aidan, Samuels, Jade, Aflorei, Elena Daniela, Barry, Sayka, Dénes, Judit, Pernicova, Ida, Stiles, Craig E., Trivellin, Giampaolo, McCloskey, Ronan, Ajzensztejn, Michal, Abid, Noina, Akker, Scott A., Mercado, Moises, Cohen, Mark, Thakker, Rajesh V., Baldeweg, Stephanie, Barkan, Ariel, Musat, Madalina, Levy, Miles, Orme, Stephen M., Unterländer, Martina, Burger, Joachim, Kumar, Ajith V., Ellard, Sian, McPartlin, Joseph, McManus, Ross, Linden, Gerard J., Atkinson, Brew, Balding, David J., Agha, Amar, Thompson, Chris J., Hunter, Steven J., Thomas, Mark G., Morrison, Patrick J., and Korbonits, Márta

Published
2017
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