A Novel Autosomal Recessive Candidate Gene Responsible for RASopathy-Like Phenotype and Bone Marrow Failure: RASA3

Abstract

Although many genetic etiologies, such as Fanconi anemia, Shwachman–Diamond syndrome, dyskeratosis congenita, and Diamond–Blackfan anemia, from hereditary bone marrow failure are known today, the responsible gene remains unknown in a significant part of these patients. A 6-year-old girl, whose parents were first-cousin consanguineous, was referred to the pediatric hematology department due to growth retardation, thrombocytopenia, neutropenia, and anemia. The patient had low-set ears, pectus excavatum inferiorly, and cafe-au-lait spots. In whole-exome analysis, p.K385T (c.1154A > C) variant in the RASA3 gene was detected as homozygous. The amino acid position of the alteration is located in the conserved and ordered region, corresponding to the Ras GTPase activation domain (Ras-GAP) in the center of the protein. Importantly, most of in silico prediction tools of pathogenicity predicts the variant as damaging. RASopathies, which are characterized by many common clinical findings, such as atypical facial features, growth delays, and heart defects, are a group of rare genetic diseases caused by mutations in the genes involved in the Ras-MAPK pathway. The findings in this patient were consistent with the RASopathy-like phenotype and bone marrow failure. Interestingly, enrichment of RASopathy genes was observed in the RASA3 protein–protein interaction network. Furthermore, the subsequent topological clustering revealed a putative function module, which further implicates RASA3 in this disease as a novel potential causative gene. In this context, the detected RASA3 mutation could be manifesting itself clinically as the observed phenotype by disrupting the functional cooperation between the RASA3 protein and its interaction partners. Relatedly, current literature also supports the obtained findings. Overall, this study provides new insights into RASopathy and put forward the RASA3 gene as a novel candidate gene for this disease group.

Keywords

RASA3 - RASopathy - bone marrow failure - p.K385T - c.1154A > C

Publication History

Received: 04 September 2022

Accepted: 28 March 2023

Article published online:
26 October 2023

• References

• 1 Moore CA, Krishnan K. Bone Marrow Failure. July 13, 2021. In: StatPearls [Internet]. Treasure Island, FL StatPearls Publishing; January 2021. PMID: 29083589
• 2 Yarwood S, Bouyoucef-Cherchalli D, Cullen PJ, Kupzig S. The GAP1 family of GTPase-activating proteins: spatial and temporal regulators of small GTPase signalling. Biochem Soc Trans 2006; 34 (Pt 5): 846-850
• 3 Blanc L, Ciciotte SL, Gwynn B. et al. Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis. Proc Natl Acad Sci U S A 2012; 109 (30) 12099-12104
• 4 Brindley EC, Papoin J, Kennedy L. et al. Rasa3 regulates stage-specific cell cycle progression in murine erythropoiesis. Blood Cells Mol Dis 2021; 87: 102524
• 5 Köhler S, Gargano M, Matentzoglu N. et al. The Human Phenotype Ontology in 2021. Nucleic Acids Res 2021; 49 (D1): D1207-D1217
• 6 Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 2010; 11: 548
• 7 Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11 (04) 361-362
• 8 Letunic I, Khedkar S, Bork P. SMART: recent updates, new developments and status in 2020. Nucleic Acids Res 2021; 49 (D1): D458-D460
• 9 Oates ME, Romero P, Ishida T. et al. D²P²: Database of Disordered Protein Predictions. Nucleic Acids Res 2013; 41 (Database issue): D508-D516
• 10 UniProt Consortium T. UniProt: the universal protein knowledgebase. Nucleic Acids Res 2018; 46 (05) 2699
• 11 Szklarczyk D, Gable AL, Nastou KC. et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49 (D1): D605-D612 Erratum in: Nucleic Acids Res. 2021 Oct 11;49(18):10800
• 12 Grissa D, Junge A, Oprea TI, Jensen LJ. Diseases 2.0: a weekly updated database of disease-gene associations from text mining and data integration. Database (Oxford) 2022; 2022: baac019
• 13 Shannon P, Markiel A, Ozier O. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13 (11) 2498-2504
• 14 Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 2003; 4: 2
• 15 Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res 2019; 47 (W1): W199-W205
• 16 Ashburner M, Ball CA, Blake JA. et al; The Gene Ontology Consortium. Gene Ontology: tool for the unification of biology. Nat Genet 2000; 25 (01) 25-29
• 17 Jourquin J, Duncan D, Shi Z, Zhang B. GLAD4U: deriving and prioritizing gene lists from PubMed literature. BMC Genomics 2012; 13 (Suppl 8, Suppl 8): S20
• 18 Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat Rev Cancer 2010; 10 (12) 842-857
• 19 Schurmans S, Polizzi S, Scoumanne A, Sayyed S, Molina-Ortiz P. The Ras/Rap GTPase activating protein RASA3: from gene structure to in vivo functions. Adv Biol Regul 2015; 57: 153-161
• 20 Fukuda M, Mikoshiba K. The function of inositol high polyphosphate binding proteins. BioEssays 1997; 19 (07) 593-603
• 21 Ye KJ, Dai J, Liu LY, Peng MJ. Network–based gene function inference method to predict optimal gene functions associated with fetal growth restriction. Mol Med Rep 2018; 18 (03) 3003-3010
• 22 Sonawane AR, Weiss ST, Glass K, Sharma A. Network medicine in the age of biomedical big data. Front Genet 2019; 10: 294
• 23 Iwashita S, Kobayashi M, Kubo Y. et al. Versatile roles of R-Ras GAP in neurite formation of PC12 cells and embryonic vascular development. J Biol Chem 2007; 282 (06) 3413-3417
• 24 Maertens O, Cichowski K. An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer. Adv Biol Regul 2014; 55: 1-14