Oriol Calvete1,2, Maite Herraiz3, Jose Reyes4, Ana Patiño5, Javier Benitez6,7. 1. Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. 2. Biomedical Research Networking Center on Rare Diseases (CIBERER), 28029, Madrid, Spain. 3. Department of Gastroenterology, University Clinic of Navarra, 31008, Pamplona, Spain. 4. Department of Gastroenterology, Hospital INCA, 07300, Majorca, Spain. 5. Department of Pediatrics and Clinical Genetics Unit, University Clinic of Navarra, 31008, Pamplona, Spain. 6. Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. jbenitez@cnio.es. 7. Biomedical Research Networking Center on Rare Diseases (CIBERER), 28029, Madrid, Spain. jbenitez@cnio.es.
Abstract
BACKGROUND: Type I gastric neuroendocrine tumors (gNETs) classically arise because of hypergastrinemia and involve destruction of parietal cells, which are responsible for gastric acid secretion through the ATP4A proton pump and for intrinsic factor production. METHODS: By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin. RESULTS: A heterozygous missense mutation in the ATP4A gene was identified. Carriers of this variant had low ferritin and vitamin B12 levels but did not develop gNETs. A second heterozygous mutation was also uncovered (PTH1R p.E546K). Carriers exhibited hypothyroidism and one of them had rheumatoid arthritis. Gastrin activates parathyroid hormone like hormone/parathyroid hormone 1 receptor (PTH1R) signaling, which is involved in gastric cell homeostasis. Activation of parathyroid hormone/PTH1R, which is upregulated by thyrotropin in the thyroid, is also involved in RANKL expression, which regulates bone homeostasis. Thyrotropin and RANKL expression were deregulated in PTH1R mutation carriers, suggesting a link between the PTH1R gene, hypothyroidism, rheumatoid arthritis, and gastric disease. Only patients with both mutations developed gNETs plus hypothyroidism and rheumatoid arthritis. CONCLUSION: Both mutations suggest that a collaborative mechanism is operative in this family, in which mutations in these genes affect the function and viability of parietal cells and lead to the achlorhydria that drives hypergastrinemia and the formation of gNETs.
BACKGROUND:Type I gastric neuroendocrine tumors (gNETs) classically arise because of hypergastrinemia and involve destruction of parietal cells, which are responsible for gastric acid secretion through the ATP4A proton pump and for intrinsic factor production. METHODS: By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin. RESULTS: A heterozygous missense mutation in the ATP4A gene was identified. Carriers of this variant had low ferritin and vitamin B12 levels but did not develop gNETs. A second heterozygous mutation was also uncovered (PTH1Rp.E546K). Carriers exhibited hypothyroidism and one of them had rheumatoid arthritis. Gastrin activates parathyroid hormone like hormone/parathyroid hormone 1 receptor (PTH1R) signaling, which is involved in gastric cell homeostasis. Activation of parathyroid hormone/PTH1R, which is upregulated by thyrotropin in the thyroid, is also involved in RANKL expression, which regulates bone homeostasis. Thyrotropin and RANKL expression were deregulated in PTH1R mutation carriers, suggesting a link between the PTH1R gene, hypothyroidism, rheumatoid arthritis, and gastric disease. Only patients with both mutations developed gNETs plus hypothyroidism and rheumatoid arthritis. CONCLUSION: Both mutations suggest that a collaborative mechanism is operative in this family, in which mutations in these genes affect the function and viability of parietal cells and lead to the achlorhydria that drives hypergastrinemia and the formation of gNETs.
Authors: P W M Ho; A Goradia; M R Russell; A M Chalk; K M Milley; E K Baker; J A Danks; J L Slavin; M Walia; B Crimeen-Irwin; R A Dickins; T J Martin; C R Walkley Journal: Oncogene Date: 2014-07-21 Impact factor: 9.867
Authors: Oriol Calvete; Jose Reyes; Sheila Zuñiga; Beatriz Paumard-Hernández; Victoria Fernández; Luís Bujanda; María S Rodriguez-Pinilla; Jose Palacios; Damian Heine-Suñer; Siddharth Banka; William G Newman; Marta Cañamero; D Mark Pritchard; Javier Benítez Journal: Hum Mol Genet Date: 2015-02-11 Impact factor: 6.150
Authors: Charles G Helmick; David T Felson; Reva C Lawrence; Sherine Gabriel; Rosemarie Hirsch; C Kent Kwoh; Matthew H Liang; Hilal Maradit Kremers; Maureen D Mayes; Peter A Merkel; Stanley R Pillemer; John D Reveille; John H Stone Journal: Arthritis Rheum Date: 2008-01
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