PXD078848-1

PXD078848 is an original dataset announced via ProteomeXchange.

Title	Novel mechanistic insights into mutations that cause diseases of phosphate dysregulation
Description	Phosphate plays essential roles within the human body and levels are tightly controlled through conserved feedback loops. FGF23, a phosphate regulating hormone produced in the bone, is regulated by the glycosyltransferase, GALNT3, whose expression is sensitive to circulating phosphate levels. GALNT3-mediated glycosylation of FGF23 confers protection from inactivating furin cleavage, thus allowing intact FGF23 to modulate phosphate reabsorption in the kidneys. Mutations in either FGF23 or GALNT3 are responsible for diseases of phosphate regulation, which can lead to growth defects, skeletal malformations, soft-tissue calcifications, kidney failure and death. However, the specific effects of many of these mutations remain poorly understood and effective treatments are lacking. Here we employ an in vivo system that recapitulates the FGF23/GALNT3 axis to demonstrate the functional consequences of 11 GALNT3 patient mutations. We identify certain GALNT3 mutations that affect stability yet retain catalytic activity and thus may be targets for therapeutic approaches that enhance folding/stability. We present evidence that one previously reported pathogenic mutation is not pathogenic. We also demonstrate that two addition members of the GALNT family can glycosylate FGF23 and protect it from furin cleavage in cells. Finally, we examine 3 patient-derived FGF23 mutations and show they have unique effects on stability or secretion. This study provides detailed mechanistic information regarding patient mutations in both GALNT3 and FGF23 that result in disease and a functional platform for developing new approaches to treat diseases of phosphate dysregulation.
HostingRepository	PRIDE
AnnounceDate	2026-07-24
AnnouncementXML	Submission_2026-07-24_08:33:21.686.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD078848
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Liping Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	O-(N-acetylamino)galactosyl-L-serine
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-26 01:42:30	ID requested
⏵ 1	2026-07-24 08:33:22	announced

10.6019/PXD078848;

submitter keyword: GALNT3-mediated glycosylation of FGF23, phosphate dysregulation, GALNT3,FGF23

Kelly G. Ten Hagen
contact affiliation	NIDCR, NIH
contact email	zhanglip@mail.nih.gov
lab head
Liping Zhang
contact affiliation	NIDCR/NIH
contact email	zhanglip@mail.nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD078848
     1. Label: PRIDE project
     2. Name: Novel mechanistic insights into mutations that cause diseases of phosphate dysregulation