Mutational analysis of consanguineous families and their targeted therapy against dwarfism

Abstract

Dwarfism is a medical term used to describe individuals with a height-vertex measurement that falls below two standard deviations (−2SD) or the third percentile for their gender and age. Normal development of growth is a complicated dynamic procedure that depends upon the coordination of different aspects involving diet, genetics, and biological aspects like hormones in equilibrium. Any severe or acute pathologic procedure may disturb the individual’s normal rate of growth. In this research, we examined four (A–D) Pakistani consanguineous families that exhibited syndromic dwarfism, which was inherited in an autosomal recessive pattern. The genomic DNA of each family member was extracted by using phenol-chloroform and Kit methods. Whole Exome Sequencing (WES) of affected family members (IV-11, III-5, IV-4 and III-13) from each group was performed at the Department of Medical Genetics, University of Antwerp, Belgium. After filtering the exome data, the mutations in PPM1F, FGFR3, ERCC2, and PCNT genes were determined by Sanger sequencing of each gene by using specific primers. Afterward, FGFR3 was found to be a suitable drug target among all the mutations to treat achondroplasia also known as disproportionate dwarfism. BioSolveIT softwares were used to discover the lead active inhibitory molecule against FGFR3. This research will not only provide short knowledge to the concerned pediatricians, researchers, and family physicians for the preliminary assessment and management of the disorder but also provide a lead inhibitor for the treatment of disproportionate dwarfism.

Communicated by Ramaswamy H. Sarma

Keywords:

• Achondroplasia
• consanguineous families
• dwarfism
• fibroblast growth factor receptor 3
• whole exome sequencing

Acknowledgment

The authors also would like to extend their heartfelt appreciation to BioSolveIT, Germany, for their invaluable support and generous provision of access to their state-of-the-art drug design tools namely SeeSAR and InfiniSee.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Institutional review board statement

The study design entitled ‘Mutational analysis of consanguineous families and their targeted therapy against dwarfism’ was approved by the Institutional Ethic Committee (approval number: PMAS-AAUR/D.FoS/269), Faculty of Sciences, Arid Agriculture University, Rawalpindi, Pakistan. The researchers ensure strict adherence to approved protocols by Institutional Ethics Committee for human sampling and their usage.

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP.2/93/44.