Noonan syndrome pathophysiology: Difference between revisions
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==Pathophysiology== | ==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.<ref name="pmid16124853">{{cite journal| author=Tartaglia M, Gelb BD| title=Noonan syndrome and related disorders: genetics and pathogenesis. | journal=Annu Rev Genomics Hum Genet | year= 2005 | volume= 6 | issue= | pages= 45-68 | pmid=16124853 | doi=10.1146/annurev.genom.6.080604.162305 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16124853 }} </ref> | 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.<ref name="pmid16124853">{{cite journal| author=Tartaglia M, Gelb BD| title=Noonan syndrome and related disorders: genetics and pathogenesis. | journal=Annu Rev Genomics Hum Genet | year= 2005 | volume= 6 | issue= | pages= 45-68 | pmid=16124853 | doi=10.1146/annurev.genom.6.080604.162305 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16124853 }} </ref> | ||
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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. | 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.<ref name="pmid11992261">{{cite journal| author=Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I et al.| title=PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. | journal=Am J Hum Genet | year= 2002 | volume= 70 | issue= 6 | pages= 1555-63 | pmid=11992261 | doi=10.1086/340847 | pmc=PMC379142 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11992261 }} </ref> | 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.<ref name="pmid11992261">{{cite journal| author=Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I et al.| title=PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. | journal=Am J Hum Genet | year= 2002 | volume= 70 | issue= 6 | pages= 1555-63 | pmid=11992261 | doi=10.1086/340847 | pmc=PMC379142 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11992261 }} </ref> | ||
Revision as of 23:05, 7 November 2013
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Noonan syndrome pathophysiology On the Web |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian
Overview
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
|pmid=value (help).
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