This report describes Noonan syndrome 12, a subtype of Noonan syndrome that exhibits autosomal dominant inheritance. The human gene implicated is RRAS2, which encodes a member of the R-Ras subfamily of Ras-like small GTPases. There is one high-scoring fly ortholog, Dmel\Ras64B, for which multiple genetic reagents, including classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Additionally, there are multiple low-scoring fly orthologs.
Multiple UAS constructs of the human Hsap\RRAS2 gene, including wild-type and a human disease-implicated variant, have been introduced into flies. See the 'Disease-Implicated Variants' table below.
Retina-specific expression of wild-type Hsap\RRAS2 has no phenotype in the adult eye. Retina-specific expression of a Hsap\RRAS2 construct bearing the variant G23V is lethal, suggesting a toxic gain-of-function in the variant protein.
[updated May 2024 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 12; NS12](https://omim.org/entry/618624)
[RELATED RAS VIRAL ONCOGENE HOMOLOG 2; RRAS2](https://omim.org/entry/600098)
Noonan syndrome 12 (NS12) is characterized by macrocephaly and a recognizable facies, including hypertelorism, downslanting palpebral fissures, and low-set ears, as well as other features consistent with a Noonan syndrome diagnosis. Inter- and intrafamilial variability has been observed (Capri et al., 2019, pubmed:31130282; Niihori et al., 2019, pubmed:31130285 [from MIM:618624; 2024.05.29]
Noonan syndrome-12 (NS12) is caused by heterozygous mutation in the RRAS2 gene on chromosome 11p15. [from MIM:618624; 2024.05.29]
The RRAS2 gene encodes a member of the R-Ras subfamily of Ras-like small GTPases. The encoded protein associates with the plasma membrane and may function as a signal transducer. This protein may play an important role in activating signal transduction pathways that control cell proliferation. Mutations in this gene are associated with the growth of certain tumors. [provided by RefSeq, Apr 2010]
High-scoring ortholog of human RRAS2, moderate scoring ortholog of human RRAS, HRAS, KRAS, NRAS (many Drosophila to many human).
