Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Saturday, May 27, 2006

Noonan Syndrome - Part Three


Normal allelic variants: Tartaglia et al (2001) identified the PTPN11 gene as causative of Noonan syndrome. The gene comprises 15 exons, with two tandemly arranged SRC-2 homology 2 (SH2) domains at the N terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a carbody tail with two TP sites and a proline-rich stretch. The SH2-PTP interaction maintains TP sites and a proline-rich stretch. The SH2-PTP interaction maintains the protein in an inactive state.

Pathologic allelic variants: Missense mutations in PTPN11 were identified in 50% of individuals examined. Ninety-five percent of mutations alter residues at or close to the SH2-PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein and cause catalytic activation and gain of function. Five percent of the mutations alter sensitivity to activation from binding partners. One 3-bp deletion has been described [
Tartaglia et al 2002; Fragale et al 2004].

Normal gene product: PTPN11 encodes tyrosine-protein phosphatase non-receptor type II (SHP-2), a widely expressed extra-cellular protein. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis [Tartaglia et al 2002, Fragale et al 2004].

Abnormal gene product: Activation of tyrosine-protein phosphatase non-receptor type II stimulates epidermal growth factor-mediated RAS/ERK/MAPK activation, increasing cell proliferation [
Tartaglia et al 2002, Fragale et al 2004].


Normal allelic variants: The gene has four exons spanning 45 kb. Alternative splicing results in two isoforms (4a and 4b) that differ at the C terminus. In 98% of transcripts, exon 4a is spliced out and only exon 4b is available for translation into protein. The effector or switch domains are part of exons 1 and 2, while binding to guanine nucleotide exchange factors occurs in exon 3.

Pathologic allelic variants: Somatic KRAS and NRAS mutations have been found in myeloid malignancies and other cancers. The association between abnormal Kras and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function mutations confer similar biochemical and cellular phenotypes as Noonan syndrome-associated SHP-2 mutations.

Normal gene product: Ras proteins regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. They are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth and death of cells.

Abnormal gene product: The abnormal K-Ras protein induces hypersensitivity of primary hematopoietic progenitor cells to growth factors and deregulates signal transduction in a cell lineage-specific manner. Strong gain-of-function KRAS mutations may be incompatible with life.

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

National Library of Medicine Genetics Home Reference
Noonan syndrome

The Noonan Syndrome Support Group
PO Box 145 Upperco, MD 21155
Phone: 888-686-2224; 410-374-5245

Human Growth Foundation
997 Glen Cove Avenue Suite 5
Glen Head NY 11545
Phone: 800-451-6434 Fax: 516-671-4055

The MAGIC Foundation
6645 West North Avenue
Oak Park, IL 60302
Phone: 800-362-4423; 708-383-0808 Fax: 708-383-0899


Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.

Published Statements and Policies Regarding Genetic Testing
No specific guidelines regarding genetic testing for this disorder have been developed.
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Chapter Notes

Revision History

16 May 2006 (cd) Revision: KRAS testing clinically available
1 May 2006 (ja) Revision: mutations in KRAS cause Noonan syndrome
9 March 2006 (me) Comprehensive update posted to live Web site
17 December 2003 (me) Comprehensive update posted to live Web site
15 November 2001 (me) Review posted to live Web site
2 August 2001 (ja) Original submission

Original Complete Article