Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy

Saber Imani; Jingliang Cheng; Marzieh Dehghan Shasaltaneh; Chunli Wei; Lisha Yang; Shangyi Fu; Hui Zou; Md Asaduzzaman Khan; Xianqin Zhang; Hanchun Chen; Dianzheng Zhang; Chengxia Duan; Hongbin Lv; Yumei Li; Rui Chen; Junjiang Fu

doi:10.18632/oncotarget.22343

Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in Stargardt4-like macular dystrophy

Oncotarget. 2017 Nov 9;9(1):122-141. doi: 10.18632/oncotarget.22343. eCollection 2018 Jan 2.

Authors

Saber Imani^{1

2

3}, Jingliang Cheng², Marzieh Dehghan Shasaltaneh^{4

5}, Chunli Wei^{2

6}, Lisha Yang², Shangyi Fu^{7

8}, Hui Zou^{1

2}, Md Asaduzzaman Khan², Xianqin Zhang², Hanchun Chen⁹, Dianzheng Zhang¹⁰, Chengxia Duan¹¹, Hongbin Lv¹¹, Yumei Li⁸, Rui Chen⁸, Junjiang Fu^{1

2

6}

Affiliations

¹ Hunan Normal University Medical College, Changsha, Hunan, China.
² Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China.
³ Chemical Injuries Research Center, Baqiyatallah Medical Sciences University, Tehran, Iran.
⁴ Laboratory of Neuro-organic Chemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
⁵ Laboratory of Systems Biology and Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
⁶ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
⁷ The Honors College, University of Houston, Houston, TX, USA.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁹ Department of Biochemistry, School of Life Sciences & the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
¹⁰ Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA.
¹¹ Department of Ophthalmology, First Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.

Abstract

Stargardt disease-4 (STGD4) is an autosomal dominant complex, genetically heterogeneous macular degeneration/dystrophy (MD) disorder. In this paper, we used targeted next generation sequencing and multiple molecular dynamics analyses to identify and characterize a disease-causing genetic variant in four generations of a Chinese family with STGD4-like MD. We found a novel heterozygous missense mutation, c.734T>C (p.L245P) in the PROM1 gene. Structurally, this mutation most likely impairs PROM1 protein stability, flexibility, and amino acid interaction network after changing the amino acid residue Leucine into Proline in the basic helix-loop-helix leucine zipper domain. Molecular dynamic simulation and principal component analysis provide compelling evidence that this PROM1 mutation contributes to disease causativeness or susceptibility variants in patients with STGD4-like MD. Thus, this finding defines new approaches in genetic characterization, accurate diagnosis, and prevention of STGD4-like MD.

Keywords: PROM1; missense mutation; molecular modeling; next generation sequencing; stargardt disease-4 (STGD4).