Aberrant HRAS transcript processing underlies a distinctive phenotype within the RASopathy clinical spectrum

作者：Pantaleoni Francesca; Lev Dorit; Cirstea Ion C; Motta Marialetizia; Lepri Francesca Romana; Bottero Lisabianca; Cecchetti Serena; Linger Ilan; Paolacci Stefano; Flex Elisabetta; Novelli Antonio; Care Alessandra; Ahmadian Mohammad R; Stellacci Emilia^*; Tartaglia Marco^*

来源：Human Mutation, 2017, 38(7): 798-804.

DOI：10.1002/humu.23224

• Costello syndrome
• HRAS
• RASopathies
• RAS signaling
• transcript processing

RASopathies are a group of rare, clinically related conditions affecting development and growth, and are caused by germline mutations in genes encoding signal transducers and modulators with a role in the RAS signaling network. These disorders share facial dysmorphia, short stature, variable cognitive deficits, skeletal and cardiac defects, and a variable predisposition to malignancies. Here, we report on a de novo 10-nucleotide-long deletion in HRAS (c.481_490delGGGACCCTCT, NM_176795.4; p.Leu163ProfsTer52, NP_789765.1) affecting transcript processing as a novel event underlying a RASopathy characterized by developmental delay, intellectual disability and autistic features, distinctive coarse facies, reduced growth, and ectodermal anomalies. Molecular and biochemical studies demonstrated that the deletion promotes constitutive retention of exon IDX, which is generally skipped during HRAS transcript processing, and results in a stable and mildly hyperactive GDP/GTP-bound protein that is constitutively targeted to the plasma membrane. Our findings document a new mechanism leading to altered HRAS function that underlies a previously unappreciated phenotype within the RASopathy spectrum.

• 出版日期2017-7