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. 2022 Jan;43(1):3-15.
doi: 10.1002/humu.24287. Epub 2021 Oct 11.

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

Koki Nagai  1 , Tetsuya Niihori  1 , Nobuhiko Okamoto  2 , Akane Kondo  3 , Kenichi Suga  4 , Tomoko Ohhira  5 , Yasunobu Hayabuchi  4 , Yukako Homma  4 , Ryuji Nakagawa  4 , Toshinobu Ifuku  5 , Taiki Abe  1 , Takeshi Mizuguchi  6 , Naomichi Matsumoto  6 , Yoko Aoki  1
Affiliations

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

Koki Nagai et al. Hum Mutat. 2022 Jan.

Abstract

Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

Keywords: Costello syndrome; G3 domain; HRAS; intragenic duplication; switch II region.

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References

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