Structural and functional insights into a novel homozygous missense pathogenic variant in CUL7 identified in consanguineous Pakistani family

Abstract

3M syndrome is a rare genetic familial disorder characterized by short stature, growth retardation, facial dysmorphism, skeletal abnormalities, fleshy protruding heels, and normal intelligence, caused by mutations in the CUL7, OBSL1 and CCDC8 genes. In the present study, a novel homozygous missense variant of CUL7 (NP_001161842.1, c.4493T > C, p.L1498P) has been identified in a consanguineous Pakistani family by whole exome sequencing. In silico structural evaluation, molecular docking and simulation studies of mutant CUL7 provides substantial evidence about its crucial role in the progression of discussed ailment. The newly discovered variant significantly altered the protein’s three dimensional structure, leading to abnormal interaction with binding proteins. This computational and experimental investigation provides useful information to drug developers for the synthesis of novel therapeutics against the discussed ailment.

Communicated by Ramaswamy H. Sarma

Keywords:

• 3M syndrome
• skeletal dysplasia
• exome sequencing
• novel mutation in CUL7 gene
• bioinformatics
• in silico structural and functional studies
• molecular docking studies
• molecular dynamic simulation assay

Acknowledgements

The Authors acknowledge the patients and their family for participating in the study. We are highly thankful to Prof. Carlos Adam Conte of the Federal University of Rio de Janeiro, Brazil, as he was very helpful in critically reviewing and polishing the article in terms of English language.

Authors’ Contributions

Zaka A: Blood sampling and Experimental work, initial manuscript writeup. Yousaf M: In silico structural and functional analysis of proteins and manuscript preparation. Shahzad S: Experimental work supervision/guidance, Manuscript preparation and editing, data analysis. Rao H Z: Collected and interpreted clinical data. Foo J N: NGS data analysis. Compilation of data and manuscript editing. Siddiqi S: Experimental work supervision, NGS Data analysis, Edited -manuscript.

Disclosure Statement

The authors declare no conflict of interest and no competing interests regarding publication of this research article.

Funding

The research was conducted in the absence of any governmental funding.

Ethical Approval and Consent to Participate

Consent for Publication

Consent for publication was obtained from the participating families.

Availability of Data and Materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The present research study is in compliance with Ethical standards and approved from the Ethical Review Committee of International Islamic University, Islamabad.