Zampino, G. et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum. Mutat. 28, 265-272

University of Naples Federico II, Napoli, Campania, Italy
Human Mutation (Impact Factor: 5.14). 03/2007; 28(3):265-72. DOI: 10.1002/humu.20431
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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.

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Available from: Gilda Cobellis
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    • "Specific amino acid substitutions, particularly those strongly inducing oncogenic cell transformation, may result in an early lethal phenotype [Lo et al., 2008]. In contrast, rarer HRAS mutations are associated with an attenuated phenotype as reported for p.Thr58 and p.Ala146 [Zampino et al., 2007; Gripp et al., 2008, 2012a], or a slightly variant phenotype with p.Glu37dup [Gremer et al., 2010a]. HRAS serves as signal transducer by alternating between an active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound state. "
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    ABSTRACT: Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolytic HRAS activity resulting in constitutive activation. "Gain-of-function" and "hyperactivation" concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one. None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS(Gly60Asp) binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent. Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015 · American Journal of Medical Genetics Part A
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    • "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]. "
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    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.
    Full-text · Article · Mar 2015 · American Journal of Medical Genetics Part A
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    • "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]. "
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    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.
    Full-text · Article · Jan 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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