Dataset Information

Phosphoproteomics reveals the functional role of the PTPN11 p.N308S (c.923A>G) Variant in a Noonan syndrome pedigree

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jiewei Luo

PROVIDER: PXD068242 | iProX | Wed Sep 10 00:00:00 BST 2025

REPOSITORIES: iProX

ACCESS DATA

Similar Datasets

Project description:The callipyge phenotype is a monogenic muscular hypertrophy that is only expressed in heterozygous sheep receiving the CLPG mutation from their sire. The wild-type phenotype of CLPG/CLPG animals is thought to result from translational inhibition of paternally expressed DLK1 transcripts by maternally expressed miRNAs. To identify the miRNA responsible for this trans-effect, we used high-throughput sequencing to exhaustively catalogue miRNAs expressed in skeletal muscle of sheep of the four CLPG genotypes. We have identified 747 miRNA species of which 110 map to the DLK1-GTL2 or callipyge domain. We demonstrate that the latter are imprinted and preferentially expressed from the maternal allele. We show that the CLPG mutation affects their level of expression in cis (~3.2-fold increase) as well as in trans (~1.8-fold increase). In CLPG/CLPG animals, miRNAs from the DLK1-GTL2 domain account for ~20% of miRNAs in skeletal muscle.We show that the CLPG genotype affects the levels of A to I editing of at least five pri-miRNAs of the DLK1-GTL2 domain, but that levels of editing of mature miRNA are always minor. We present suggestive evidence that the miRNAs from the domain target the ORF of DLK1 thereby causing the trans-inhibition underlying polar overdominance. We highlight the limitations of high-throughput sequencing for digital gene expression profiling as a result of biased and inconsistent amplification of specific miRNAs. These data were used to confirm the expression levels found by the high-throughput sequencing analysis. A total of 8 samples (two animals per callipyge genotype) were analysed using the miRCury LNA microRNA array (Exiqon). On each array, the test sample labelled with Hy3 was hybridized on one channel, and a pool made with the 8 test samples (labelled with Hy5) was used on the other channel as a reference for normalization. The callipyge mutation (C) is a SNP localised in an imprinted domain. Thus, heterozygous animals will have different phenotypes. The following 4 genotypes were analyzed in this study: NN: Wild-type (+mat/+pat) CN: Maternal heterozygous (Cmat/+pat) NC: Paternal heterozygous (+mat/Cpat) CC: Homozygous mutant (Cmat/Cpat)

Dataset Information

Phosphoproteomics reveals the functional role of the PTPN11 p.N308S (c.923A>G) Variant in a Noonan syndrome pedigree

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets