Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome
The canonical G406R mutation that increases Ca<sup>2+</sup> influx through the CACNA1C-encoded Ca<sub>V</sub>1.2 Ca<sup>2+</sup> channel underlies the multisystem disorder Timothy syndrome (TS), characterized by life-threatening arrhythmias. Severe episodic hypoglycemia is among the poorly characterized non-cardiac TS pathologies. While hypothesized from increased Ca<sup>2+</sup> influx in pancreatic beta cells and consequent hyperinsulinism, this hypoglycemia mechanism is undemonstrated because of limited clinical data and lack of animal models. We generated a Ca<sub>V</sub>1.2 G406R knockin mouse model that recapitulates key TS features, including hypoglycemia. Unexpectedly, these mice do not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. Patient data confirm the absence of hyperinsulinism. We discover multiple alternative contributors, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic control of glucose homeostasis. These data provide new insights into contributions of Ca<sub>V</sub>1.2 channels and reveal integrated consequences of the mutant channels driving life-threatening events in TS.
Authors
- Renan Pereira de Lima (ORCID: https://orcid.org/0000-0001-9653-7037)
- Timothy E. McGraw (ORCID: https://orcid.org/0000-0001-9748-263X)
- Daniel S. Sinden (ORCID: https://orcid.org/0000-0003-1287-367X)
- Paul Thornton (ORCID: https://orcid.org/0000-0002-9706-5665)
- Ang Li (ORCID: https://orcid.org/0000-0003-0359-3510)
- Geoffrey S. Pitt (ORCID: https://orcid.org/0000-0003-2246-0289)
- Qian Wei (ORCID: https://orcid.org/0000-0001-5948-0174)
- Maiko Matsui (ORCID: https://orcid.org/0000-0001-9706-8244)
- James C. Lo (ORCID: https://orcid.org/0000-0003-0244-1670)
- Aravind R. Gade
- Steven O. Marx (ORCID: https://orcid.org/0000-0002-0577-6030)
- Allison Galante (ORCID: https://orcid.org/0000-0002-6201-3945)
- Nicolás Gómez-Banoy (ORCID: https://orcid.org/0000-0002-3552-1768)
- Lauren E. Lynch (ORCID: https://orcid.org/0000-0002-5371-335X)
- Alfonso Rubio‐Navarro (ORCID: https://orcid.org/0000-0001-5677-3123)
- Patrick Towers
- Isabella DiStefano
- Katherine W. Timothy
- Kenneth E. Johnson
- Adam S. Barnett
- Honggang Wang (ORCID: https://orcid.org/0000-0003-4761-0407)
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Cornell University (US)
- Cook Children's Medical Center (US)
- Duke Medical Center (US)
- Duke University Hospital (US)
- Weill Cornell Medicine (US)
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1038/s41467-024-52885-3
- Citations
- 4
- Primary Topic
- Genomic variations and chromosomal abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 2.20
Funders
- National Heart, Lung, and Blood Institute