Pancytopenia, Recurrent Infection, Poor Wound Healing, Heterotopia of the Brain Probably Associated with A Candidate Novel de Novo CDC42 Gene Defect: Expanding the Molecular and Phenotypic Spectrum

• Published in: Genes 2021-02, Vol.12 (2), p.294
• Main Authors: Asiri, Abdulaziz, Alwadaani, Deemah, Umair, Muhammad, Alhamoudi, Kheloud M, Almuhanna, Mohammed H, Nasir, Abdul, Alrfaei, Bahauddeen M, Al Tuwaijri, Abeer, Barhoumi, Tlili, Alyafee, Yusra, Almuzzaini, Bader, Aldrees, Mohammed, Ballow, Mariam, Alayyar, Latifah, Al Abdulrahman, Abdulkareem, Alhaidan, Yazeid, Al Ghasham, Nahlah, Al-Ajaji, Sulaiman, Alsalamah, Mohammad, Al Suwairi, Wafa, Alfadhel, Majid
• Format: Article
• Language: English
• Subjects: CDC42 gene; Cdc42 protein; Cell adhesion & migration; Cell cycle; Cell division; Cell migration; Cycle protein; Deoxyribonucleic acid; DNA; Epidermal growth factor; Etiology; Families & family life; Fibroblasts; Genetic counseling; Genomes; Homology; Immune response; Infections; Molecular modelling; Mutation; Pancytopenia; Population studies; Protein structure; Proteins; Recurrent infection; Secondary structure; Software; Statistical analysis; Tumor necrosis factor-TNF; Variance analysis; Wound healing
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes12020294

CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the gene associated with aberrant cell migration and immune response.