Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome

Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
Human Mutation (Impact Factor: 5.14). 03/2007; 28(3):265-72. DOI: 10.1002/humu.20431
Source: PubMed

ABSTRACT Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

Download full-text


Available from: Gilda Cobellis, Sep 28, 2015
61 Reads
  • Source
    • "Similarly to what is observed in CS, caused by a narrow spectrum of missense HRAS mutations [Aoki et al., 2005; Estepp et al., 2006; Gripp et al., 2006; Zampino et al., 2007], such phenotypic homogeneity reflects the genetic homogeneity of this disorder, with all cases being associated with the c.4A>G change [Cordeddu et al., 2009; Komatsuzaki et al., 2010; Gripp et al., 2013]. So far, less than 50 SHOC2 mutation-positive patients have been reported [Cordeddu et al., 2009; Komatsuzaki et al., 2010; Baldassarre et al., 2014; Gargano et al., 2014; Takenouchi et al., 2014; Zmolikova et al., 2014], with malignancies documented in two [Ekvall et al., 2011; Gripp et al., 2013]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2015; 167(8). DOI:10.1002/ajmg.a.37082 · 2.16 Impact Factor
  • Source
    • "Mutations generally affect Gly 12 and result in enhanced signal flow through the MAPK and PI3K-AKT signaling cascades [Rosenberger et al., 2009]. Accordingly , CS belongs to the so-called RAS opathies, a group of clinically related developmental disorders sharing reduced linear growth, dysmorphic facial features, congenital heart defects, skeletal and ectodermal anomalies, and a variable degree of cognitive deficits [Tartaglia and Gelb, 2005, 2010; Estep et al., 2006; Gripp et al., 2006; Kerr et al., 2006; Kratz et al., 2007; Schubbert et al., 2007; Zampino et al., 2007; Rauen, 2013]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly12 promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades. In general, the cognitive profile in CS is characterized by intellectual disability ranging from mild to severe impairment. The first published descriptions of behavior in CS children underlined the presence of irritability and shyness at younger ages with sociable personality and good empathic skills after 4–5 years of age, however some recent studies have reported autistic traits. We report on a 7-year-old boy heterozygous for a rare duplication of codon 37 (p.E37dup) in HRAS, manifesting impaired social interaction and non-verbal communication and with circumscribed interests. These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2015; 168(1). DOI:10.1002/ajmg.b.32279 · 3.42 Impact Factor
  • Source
    • "Rsk2, the protein that is mutated in CLS, is phosphorylated by the Erks and functions downstream of the Ras–MEK–Erk signalling pathway (Anjum and Blenis, 2008). Intriguingly, many CLS patients display a prominent forehead, broad and soft hands with stubby and tapering fingers, cardiovascular defects, and cognitive dysfunction (Reynolds et al., 1986; Hanauer and Young, 2002; Tartaglia and Gelb, 2005; Bentires-Alj et al., 2006; Zampino et al., 2007), characteristics that are also seen in patients with neuro-cranio-facial-cutaneous (NCFC) syndromes, a family of disorders caused by mutation of proteins in the MAP kinase pathway (reviewed in Aoki et al. (2008)). In this regard, two of the proteins that are mutated in NCFC syndromes, the protein tyrosine phosphatase SHP2 Developmental Biology 347 (2010) 348–359 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Coffin-Lowry Syndrome (CLS) is an X-linked genetic disorder associated with cognitive and behavioural impairments. CLS patients present with loss-of-function mutations in the RPS6KA3 gene encoding the mitogen-activated protein kinase (MAPK)-activated kinase p90 ribosomal S6 kinase 2 (Rsk2). Although Rsk2 is expressed in the embryonic brain, its function remains largely uncharacterized. To this end, we isolated murine cortical precursors at embryonic day 12 (E12), a timepoint when neuronal differentiation is initiated, and knocked-down Rsk2 expression levels using shRNA. We performed similar experiments in vivo using in utero electroporations to express shRNA against Rsk2. Rsk2 knockdown resulted in a significant decrease in neurogenesis and an increase in the proportion of proliferating Pax6-positive radial precursor cells, indicating that Rsk2 is essential for cortical radial precursors to differentiate into neurons. In contrast, reducing Rsk2 levels in vitro or in vivo had no effect on the generation of astrocytes. Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS.
    Developmental Biology 11/2010; 347(2):348-59. DOI:10.1016/j.ydbio.2010.08.035 · 3.55 Impact Factor
Show more