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FB2026_01
,
released March 12, 2026
This report describes Noonan syndrome 1 (NS1), which is a subtype of Noonan syndrome; NS1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is PTPN11, which encodes a protein-tyrosine phosphatase. This gene is also associated with Noonan syndrome with multiple lentigines 1 (MIM:151100, FBhh0000041), juvenile myelomonocytic leukemia (MIM:163950, FBhh0000578), and metachondromatosis (MIM:156250). There is one high-scoring fly ortholog, csw, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated.
Using a transgenic construct of the wild-type human Hsap\PTPN11 gene under the control of a heat-shock promoter, partial heterologous rescue (functional complementation) has been demonstrated: rescue of some, but not all, phenotypes of Dmel\csw null mutants is observed.
UAS constructs of the human Hsap\PTPN11 carrying variants implicated in disease have been introduced into flies. Variant(s) implicated in human disease tested (as transgenic human gene, PTPN11): the D61G, N308D, and R498W variant forms of the human gene have been introduced into flies; the R498W variant form is also implicated in Noonan syndrome with multiple lentigines 1 (FBhh0000041). Experiments with the human variants include assessments of pharmaceutical candidates.
UAS constructs of Dmel\csw bearing mutations corresponding to Noonan syndrome 1 PTPN11 mutations have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): A72S in the fly csw gene (corresponds to A72S in the human PTPN11 gene); N287D in the fly csw gene (corresponds to N308D in the human PTPN11 gene). Both variants produce dominant gain-of-function phenotypes, which recapitulates observations in human; the A72S variant shows much stronger effects than the N287D/N308D variant. GOF variants implicated in NS1 have also been used in flies to characterize the spacing effect for long-term memory induction. In addition to the variants described above, I261V in the fly csw gene (corresponds to I282V in the human PTPN11 gene) and T73I in the fly csw gene (corresponds to T73I in the human PTPN11 gene), have been studied.
Animals homozygous for amorphic mutations of Dmel\csw die during larval and pupal stages. Germline clones in females result in maternal-effect lethality during during the embryonic stage; the embryos exhibit severe anatomical defects. Physical and genetic interactions of Dmel\csw have been described; see below and in the csw gene report.
[updated May 2021 by FlyBase; FBrf0222196]
Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002 pubmed:11992261). [from MIM:163950, 2015.04.14]
Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. [Gene Reviews, Noonan Syndrome, 2020.08.21]
[NOONAN SYNDROME 1; NS1](https://omim.org/entry/163950)
[PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11](https://omim.org/entry/176876)
Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002 pubmed:11992261). [from MIM:163950, 2015.04.14]
This form of autosomal dominant Noonan syndrome, NS1, is caused by heterozygous mutation in the PTPN11 gene. [from MIM:163950, 2015.04.14]
In more than 50% of patients with Noonan syndrome, Tartaglia et al., 2001, (pubmed:11704759) identified mutations in the PTPN11 gene. All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP-2 activity underlie the pathogenesis of Noonan syndrome. [from MIM:176876, 2015.04.14]
Many to one: 2 human to 1 Drosophila (See DIOPT, link below).
Ortholog of human PTPN11 and human PTPN6 (1 Drosophila to 2 human). Dmel\csw shares 40% identity and 52% similarity with human PTPN11, and 36% identity and 49% similarity with human PTPN6.