Mutations in Ptpn11, Encoding the Protein Tyrosine Phosphatase Shp-2 Cause Noonan Syndrome

In approximately 50% of subjects with Noonan syndrome (NS is mapped to chromosome 12q24.1) the investigators identified mutations in the 15 exon gene (PTPN11) encoding the non-receptor protein [tyrosine phosphatase (PTP) - SHP-2]. This protein has two SH2 (Src homology docking) domains and a long enzymatic domain with the sites interacting to achieve an active or inactive state of function. Diverse missense mutations were found in the third exon encoding the amino-terminal SH2 (Src homology) domain and in three exons (7,8,13) encoding the PTP domain that apparently rendered the protein constitutively active. SHP-2 is a component of several intracellular signal transduction systems involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves. The mutations associated with NS are in conserved amino acid sites in which the alteration leads to conformational changes that "lock" the protein in its enzymatically active state. The down-stream pathways that are affected by this "positive" change in enzyme activity have yet to be identified.

Tartaglia M, et al. Nat Genet 2001;29:465-468.

Editor’s Comment: Noonan syndrome (OMIM 163950) is characterized by "Turner-like" facial features, short stature, webbed neck, cubitus valgus, pulmonic stenosis (rather than coarctation of the aorta which is frequent in Turner syndrome), developmental delay, and bleeding diathesis. Since the Noonan phenotype is genetically heterogeneous, other genetic errors may exist, including mutations in the non-coding regions of PTPN11 that were not determined in the present report. The short stature and many of the skeletal abnormalities found in patients with Leri-Weill dyschondrosteosis and Turner syndrome (TS) have been attributed to haploinsufficiency of SHOX (chromosome Xpter-p22.32) either due to its deletion or to loss-of-function missense or nonsense mutations.^1,2 Given the visual similarity of the NS and TS phenotype, it will be of interest to determine if the proteins regulated by PTPN11 and SHOX interact. Might the product of SHOX be an inhibitor of SHP-2 generation or activity?

Allen Root, MD

References

1. Ross JL, et al. J Clin Endocrinol Metab 2001;86:5674-5680.

2. Rosenfeld RG. J Clin Endocrinol Metab 2001;86:5674-5680.

	www.gghjournal.com	Return to original format

*Mutations in Ptpn11, Encoding the Protein Tyrosine Phosphatase Shp-2 Cause Noonan Syndrome*
Allen Root, MD

Volume 18, Issue 2, 2002
© 2002 Prime Health Consultants, Inc.

In approximately 50% of subjects with Noonan syndrome (NS is mapped to chromosome 12q24.1) the investigators identified mutations in the 15 exon gene (PTPN11) encoding the non-receptor protein [tyrosine phosphatase (PTP) - SHP-2]. This protein has two SH2 (Src homology docking) domains and a long enzymatic domain with the sites interacting to achieve an active or inactive state of function. Diverse missense mutations were found in the third exon encoding the amino-terminal SH2 (Src homology) domain and in three exons (7,8,13) encoding the PTP domain that apparently rendered the protein constitutively active. SHP-2 is a component of several intracellular signal transduction systems involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves. The mutations associated with NS are in conserved amino acid sites in which the alteration leads to conformational changes that "lock" the protein in its enzymatically active state. The down-stream pathways that are affected by this "positive" change in enzyme activity have yet to be identified. Tartaglia M, et al. Nat Genet 2001;29:465-468. *Editor’s Comment: Noonan syndrome (OMIM 163950) is characterized by "Turner-like" facial features, short stature, webbed neck, cubitus valgus, pulmonic stenosis (rather than coarctation of the aorta which is frequent in Turner syndrome), developmental delay, and bleeding diathesis. Since the Noonan phenotype is genetically heterogeneous, other genetic errors may exist, including mutations in the non-coding regions of PTPN11 that were not determined in the present report. The short stature and many of the skeletal abnormalities found in patients with Leri-Weill dyschondrosteosis and Turner syndrome (TS) have been attributed to haploinsufficiency of SHOX (chromosome Xpter-p22.32) either due to its deletion or to loss-of-function missense or nonsense mutations.^1,2 Given the visual similarity of the NS and TS phenotype, it will be of interest to determine if the proteins regulated by PTPN11 and SHOX interact. Might the product of SHOX be an inhibitor of SHP-2 generation or activity? Allen Root, MD References* 1. Ross JL, et al. J Clin Endocrinol Metab 2001;86:5674-5680. 2. Rosenfeld RG. J Clin Endocrinol Metab 2001;86:5674-5680.