Recurring G12S Mutation of HRAS in a Chinese Child with Costello Syndrome with High Alkaline Phosphatase Level

Zhang, Huiwen; Ye, Jun; Gu, Xuefan

doi:10.1007/s10528-009-9286-7

Cited by 4 publications

(4 citation statements)

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“…Taken together, our results further delineate the detailed clinical manifestations of the c.187_207dup mutation, and confirm that this noncanonical mutation is linked to an attenuated clinical phenotype of CS. To our knowledge, this is only the second case of CS reported in China . Our study may help to clarify the genotype–phenotype correlation of CS.…”

Section: Reportmentioning

confidence: 62%

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Recurrent duplication mutation inHRAScausing mild Costello syndrome in a Chinese patient

Wang

Lin

et al. 2015

Clin Exp Dermatol

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Costello syndrome (CS; OMIM 218040) is caused by heterozygous germline mutations of HRAS (OMIM 190020).We report on a patient with sporadic CS presenting with characteristic craniofacial dysmorphism, congenital cardiopulmonary disorders, intellectual impairment, and skin abnormalities manifesting as loose redundant skin of the hands and feet, acanthosis nigricans, multiple naevi and hypotrichosis. Using Sanger sequencing for the case-parents trio, we detected a de novo insertion mutation (c.187_207dup) in HRAS, which was predicted to result in duplication of amino acids 63-69 (p.E63_D69dup). This mutation was recently described in a mild case of CS, with hyperactivation of HRAS and disrupted capacity to respond to incoming signals. Our study delineates the detailed clinical features associated with this noncanonical HRAS mutation and further expands the phenotypic spectrum of CS.

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Section: Reportmentioning

confidence: 62%

“…To our knowledge, this is only the second case of CS reported in China. 10 Our study may help to clarify the genotype-phenotype correlation of CS.…”

Section: Reportmentioning

confidence: 82%

Recurrent duplication mutation inHRAScausing mild Costello syndrome in a Chinese patient

Wang

Lin

et al. 2015

Clin Exp Dermatol

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

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Costello Syndrome

Aoki,

Niihori

2024

The RASopathies

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Recurring G12S Mutation of HRAS in a Chinese Child with Costello Syndrome with High Alkaline Phosphatase Level

Cited by 4 publications

References 10 publications

Recurrent duplication mutation inHRAScausing mild Costello syndrome in a Chinese patient

Recurrent duplication mutation inHRAScausing mild Costello syndrome in a Chinese patient

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

Costello Syndrome

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