Diversity, parental germline origin, and phenotypic spectrum of de novoHRASmissense changes in Costello syndrome

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.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

“…His parents declined autopsy examination. [Aoki et al, 2005;Estep et al, 2006;Kerr et al, 2006], three with neuroblastoma [Aoki et al, 2005;Zampino et al, 2007;van der Burgt et al, 2007], one with transitional cell carcinoma , and two unspecified tumors [Zampino et al, 2006]. Congenital heart defects.…”

“…Phenotypic features of Costello syndrome include polyhydramnios, increased birth weight, feeding problems, failure to thrive, short stature, developmental delay, pleasant personality, characteristic facial appearance, soft skin, papillomata, spatulate fingerpads, deep palmar creases, joint and skin laxity, kyphoscoliosis, pectus, and splayed fingers with ulnar deviation. Since the discovery that HRAS gene mutations cause Costello syndrome [Aoki et al, 2005], at least 150 genotyped patients have been studied [reviews by Estep et al, 2006;Gripp et al, 2006;Kerr et al, 2006;Zampino et al, 2007]. Consensus expert opinion recommends that Costello syndrome be defined solely by HRAS mutations , which differs from the molecular heterogeneity of CFC syndrome and Noonan syndrome.…”

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

“…The number of fatal cases was 5/138 patients with p.G12S, 4/6 with p.G12C, 3/17 with p.G12A, 3/4 with p.G12D, 2/2 with p.G12V, 1/1 with p.G12E and 1/1 with p.E63K. 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The mortality of patients with p.G12C or p.G12D was significantly higher than that of the patients with the more common p.G12S (P¼0.026 by Fisher's exact test). Previous studies have shown that the p.G12V substitution has the highest transformative potential (p.G12V4p.G12A, p.G12S, p.G12C, p.G12D4p.G13D) and is the most frequently found mutation in human tumors.…”

“…3 It has been suggested that the CS diagnosis should be applied only to patients with a mutation in HRAS because of the high risk of malignancies associated with HRAS mutations and the relative homogeneity of the CS phenotype. 4 A total of 14 HRAS missense mutations and one duplication mutation have been reported in 185 patients with CS 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] or congenital myopathy with excess of muscle spindles. 24 Most of these mutations have previously been reported as somatic and oncogenic mutations in various tumors.…”

C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome

“…[1][2][3][4][5][6][7][8][9] Recently, Costello syndrome has been identified as the first example of a disorder associated with activating germ-line mutations in the HRAS proto-oncogene. [10][11][12][13][14][15][16][17] In addition to Costello syndrome, a group of multiple congenital anomaly syndromes collectively named RASopathies have been shown to be associated with germline mutations in various genes of the RAS/MAPK pathway. 8,18,19 Indeed, inhibitors of a number of components of the RAS/MAPK pathway are currently being evaluated as pharmacological interventions in RASopathies.…”