A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis
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.
By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin.
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.
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.
KeywordsGastric neuroendocrine tumor PTH1R ATP4A Hypothyroidism Rheumatoid arthritis
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.
Informed consent was obtained from all patients included in the study.
Javier Benitez’s laboratory is partially funded by the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER), the H2020 BRIDGES project, and the Spanish Ministry of Health (PI12/00070 and PI16/00440).
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