title: Aberrant HRAS transcript processing underlies a distinctive phenotype within the RASopathy clinical spectrum.
abstract: 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.
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pantaleoni
authors.affiliation: The Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel.|Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universität, Dusseldorf, Germany.|Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany.
authors.forename: Ion C
authors.initials: IC
authors.lastname: Cirstea
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Marialetizia
authors.initials: M
authors.lastname: Motta
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Lepri
authors.affiliation: Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Lisabianca
authors.initials: L
authors.lastname: Bottero
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Cecchetti
authors.affiliation: The Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel.|Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Linger
authors.affiliation: Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Paolacci
authors.affiliation: Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Novelli
authors.affiliation: Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carè
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine Universität, Dusseldorf, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ahmadian
authors.affiliation: Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Emilia
authors.identifier: 0000-0003-0415-3285
authors.initials: E
authors.lastname: Stellacci
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D002658:Developmental Disabilities / Q000235:genetics*; D005091:Exons; D019066:Facies; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D018095:Germ-Line Mutation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Costello syndrome; HRAS; RAS signaling; RASopathies; transcript processing