Genetic identification and molecular modeling characterization reveal a novelPROM1mutation in Stargardt4-like macular dystrophy

// Saber Imani 1,2,3,* , Jingliang Cheng 2,* , Marzieh Dehghan Shasaltaneh 4,5,* , Chunli Wei 2,6 , Lisha Yang 2 , Shangyi Fu 7,8 , Hui Zou 1,2 , Md. Asaduzzaman Khan 2 , Xianqin Zhang 2 , Hanchun Chen 9 , Dianzheng Zhang 10 , Chengxia Duan 11 , Hongbin Lv 11 , Yumei Li 8 , Rui Chen 8 and Junjiang Fu 1,2,6 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 * These authors have contributed equally to this work Correspondence to: Junjiang Fu, email: // Keywords : stargardt disease-4 (STGD4); next generation sequencing; PROM1; missense mutation; molecular modeling Received : June 14, 2017 Accepted : August 26, 2017 Published : November 09, 2017 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.