Noonan syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian, Yazan Daaboul
Overview
Them most studied mutation leading to Noonan syndrome involves the N-SH2 domain of the SHP-2 protein involved in signal transduction as part of the RAS-MAP Kinase pathway. This mutation allows SHP-2 to become constitutively activated leading to an increase in downstream signaling and disruption of embryogenesis.
Pathophysiology
The functional pathogenesis of Noonan syndrome has been mostly elaborated in the context of PTPN11 mutations. The PTPN11 gene codes for the SHP-2 protein, a cytoplasmic SH2 domain-containing protein tyrosine phosphatase that is ubiquitous in adult and embryonic tissues. Functionally, the SHP-2 protein acts as an intracellular signal transducer that has a particularily important role during development. It is mainly involved in mesodermal patterning and gastrulation during early embryogenesis but also plays a role in the formation of terminal and skeletal structures, semilunar valvulogenesis, and hematopoiesis. It has been shown that SHP-2 positively controls the activation of the RAS/MAPK cascade, the SRC family kinase, and IL-1/TNF-dependent NF-κB activation.[1]
Structurally, the SHP-2 protein has 2 important domains an SH2 and a catalytically active PTP domain whose interaction is defective in patients with PTPN11 mutations. The SH2 domain acts as a chaperon that covers the active site of PTP basally. Because of this interaction, SHP-2 is maintained auto-inhibited except when it is required to be functional. Most of the mutations in PTPN11 affect amino acid residues close to this interaction surface between those 2 domains.
This suggests that the pathophysiology of Noonan syndrome involves a shift in the equilibrium between active and inactive SHP-2 toward the active form without any effect on the function of the protein itself.[2]
References
- ↑ Tartaglia M, Gelb BD (2005). "Noonan syndrome and related disorders: genetics and pathogenesis". Annu Rev Genomics Hum Genet. 6: 45–68. doi:10.1146/annurev.genom.6.080604.162305. PMID 16124853.
- ↑ Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I; et al. (2002). "PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity". Am J Hum Genet. 70 (6): 1555–63. doi:10.1086/340847. PMC 379142. PMID 11992261 Check
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