This report describes Noonan syndrome 3 (NS3), a sub-type of Noonan syndrome; NS3 exhibits autosomal dominant inheritance. The human gene implicated in NS3 is KRAS, one of three RAS genes in human. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers and are crucial players in many signaling networks affecting cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence. Mutations in one of the RAS genes are among the most common events in human cancers; individuals with Noonan syndrome are at a greater risk of developing childhood cancers.
In Drosophila, Ras85D is the highest-scoring ortholog of the three human RAS genes, KRAS, NRAS, and HRAS. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Ras85D. There are multiple other paralogous and orthologous genes in both species.
The human KRAS gene has not been introduced into flies.
Animals homozygous for loss-of-function alleles of Dmel\Ras85D die during the larval stage. A variant analogous to one implicated in NS3 has been created in the Drosophila gene. This mutation has been used to investigate the role of Ras85D in the formation of long-term memory, which may address aspects of the cognitive defects observed in NS3.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): V152G in the fly Ras85D gene (corresponds to V152G in the human KRAS gene). Although this C-terminal KRAS mutation is isoform-specific (affects isoform represented by UniProt P01116-2), both human protein isoforms have a valine at this position and align to the same region of the single Dmel\Ras85D isoform.
Hypertrophic cardiomyopathy is found in 20%-30% of individuals with Noonan syndrome. This aspect of NS has also been modeled in flies using the Ras85D gene; see ‘cardiomyopathy, hypertrophic (postulated), RAS-related’ (FBhh0000757).
[updated Aug. 2020 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 3; NS3](https://omim.org/entry/609942)
[KRAS PROTOONCOGENE, GTPase; KRAS](https://omim.org/entry/190070)
This form of Noonan syndrome (NS3) is caused by heterozygous mutation in the KRAS gene. [from MIM:609942; 2020.08.21]
Many to many: multiple paralogs and orthologs in both species.
