PXD068242

PXD068242 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteomics reveals the functional role of the PTPN11 p.N308S (c.923A>G) Variant in a Noonan syndrome pedigree
Description	Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, characteristic facies (hypertelorism, downward-slanting palpebral fissures), congenital heart defects (e.g., pulmonary stenosis, hypertrophic cardiomyopathy), and developmental delays. Approximately 50% of NS cases are caused by heterozygous mutations in PTPN11 encoding Src homology 2 domain-containing phosphatase 2 (SHP-2).The pathogenesis of the disease involves the phosphorylation of several proteins. In a Han Chinese NS pedigree exhibiting characteristic facies and growth retardation, whole-exome sequencing identified a heterozygous PTPN11 mutation (NM_001330437.2: c.923A>G, p.Asn308Ser) in seven affected individuals, demonstrating complete co-segregation.Structural modeling demonstrated that this mutation disrupts hydrogen bonding within the PTP domain, triggering conformational changes that destabilize SHP-2 autoinhibition. Phosphoproteomics showed that the phosphorylation level was significantly up-regulated after the mutation, and the differentially phosphorylated sites were mainly involved in multiple cross-talking pathways, which synergistically affected the activity of multiple signaling pathways, leading to the abnormalities of the broader signaling network. Functional validation in HEK293T cells confirmed RAS-MAPK pathway hyperactivation. The present study demonstrated that the PTPN11 c.923A>G (p.Asn308Ser) mutation is the responsible causative mutation in this NS family line with characteristic facies and short stature phenotype, mechanistically linking structural domain perturbations and multi-pathway phosphorylation imbalances.
HostingRepository	iProX
AnnounceDate	2025-09-10
AnnouncementXML	Submission_2025-09-10_00:10:00.079.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jiewei Luo
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-10 00:09:41	ID requested
⏵ 1	2025-09-10 00:10:00	announced

Dataset with its publication pending

submitter keyword: Noonan syndrome, PTPN11, Gene mutation, Phosphoproteomics, Bioinformatics analysis

Jiewei Luo
contact affiliation	Fujian Provincial Hospital
contact email	docluo0421@aliyun.com
lab head
Jiewei Luo
contact affiliation	Fujian Provincial Hospital
contact email	docluo0421@aliyun.com
dataset submitter

iProX dataset URI