The impact of the genetic background in the Noonan syndrome phenotype induced by K-Ras^V14I

Abstract

Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant fraction of NS-patients also develop myeloproliferative disorders. The penetrance of these defects varies considerably among patients. In this study, we have examined the effect of 2 genetic backgrounds (C57BL/6J.OlaHsd and 129S2/SvPasCrl) on the phenotypes displayed by a mouse model of NS induced by germline expression of the mutated K-Ras^V14I allele, one of the most frequent NS-KRAS mutations. Our results suggest the presence of genetic modifiers associated to the genetic background that are essential for heart development and function at early stages of postnatal life as well as in the severity of the haematopoietic alterations.

Keywords:

• developmental disorders
• genotype-phenotype correlation
• genetic backgrounds
• mouse models
• modifiers
• Noonan Syndrome
• Rasopathies
• Ras oncogenes

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgements

We thank M. Barbacid for his advice and support and I. Agudo, I. Aragón, N. Cabrera, M.C. González, M. Lamparero, P. Nogales, M. San Román, and R. Villar for technical assistance.

Funding

Work was supported by grants from Fondo de Investigación Sanitaria (PI042124, PI08–1623, PI11–02529), Autonomous Community of Madrid (GR/SAL/0349/2004), and Fundación Ramón Areces (FRA 01–09–001) to C.G. I.H.-P. was supported by PFIS grant from the Instituto de Salud Carlos III and A.J.S. by a FPU fellowship from the Spanish Ministry of Economy and Competitiveness and by the COFUND scheme of the Seventh Framework Program of the European Union (grant agreement 291820).