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

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

doi:10.18632/oncotarget.22343

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.

Highlights

Stargardt disease (STGD) is a common, heterogeneous juvenile-onset macular degeneration/ dystrophy (MD) disease with an estimated incidence of 10-12.5 per 100,000 people [1, 2]
The images of the proband are documented by fundus photography (FP), fundus autofluorescence (FA), electroretinograms (ERGs), and optical coherence tomography (OCT), which are shown in Figure 1B-1G, respectively
In this genetic analysis study, we performed Targeted exome sequencing (TES) arrays to identify the genetic defect in a Chinese family with multi-cases of Stargardt disease-4 (STGD4)-like MD retinal degenerations (M107)

Summary

Introduction

Stargardt disease (STGD) is a common, heterogeneous juvenile-onset macular degeneration/ dystrophy (MD) disease with an estimated incidence of 10-12.5 per 100,000 people [1, 2]. STGD is www.impactjournals.com/oncotarget usually characterized by decreased central vision, night blindness, mildl atrophy of the macular photoreceptor cells, underlying retinal pigment epithelium, and gradual appearance of fundus flecks in the posterior pole of the retina [3]. This STGD disease is mostly inherited as an autosomal recessive trait of STGD (arSTGD) while Stargardt disease-4 (STGD4) is an autosomal dominant trait (adSTGD), which is associated with mutations in various genes. Mutations in the PROM1 gene have been reported in other MD diseases, such as STGD4 [10, 12, 19] and cone-rod dystrophy [9,10,11], which demonstrates that mutations in same gene may manifest multiple clinical phenotypes

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Conclusion