Germline KRAS mutations cause Noonan syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Noonan syndrome is a genetic disorder characterized by short stature, facial dysmorphism, and cardiac defects.
• Heterozygous mutations in PTPN11, encoding SHP-2 phosphatase, account for about 50% of Noonan syndrome cases.
• SHP-2 is crucial in relaying signals from activated receptors to downstream effectors like Ras.

Purpose of the Study:

• To investigate novel genetic causes of Noonan syndrome and related cardio-facio-cutaneous syndrome.
• To understand the functional consequences of identified mutations in RAS pathway components.

Main Methods:

• Identification of de novo germline mutations in KRAS in patients with Noonan syndrome and cardio-facio-cutaneous syndrome.
• Biochemical characterization of recombinant mutant K-Ras proteins (V14I, T58I).
• Assessment of cellular signaling in primary hematopoietic progenitors.

Main Results:

• Discovered de novo germline KRAS mutations (V14I, T58I, D153V) in Noonan syndrome patients.
• Identified a KRAS P34R alteration in a cardio-facio-cutaneous syndrome patient.
• Mutant K-Ras proteins exhibited defective GTP hydrolysis and impaired response to GTPase activating proteins.
• Mutations led to hypersensitivity of hematopoietic progenitors to growth factors and deregulated cell signaling.

Conclusions:

• Germline KRAS mutations are a newly identified cause of Noonan syndrome spectrum disorders.
• Hyperactive Ras signaling due to these mutations is largely responsible for the developmental abnormalities.
• This expands the genetic basis of RASopathies and highlights the critical role of KRAS in human development.