Whole-exome sequencing identifies a novel homozygous frameshift mutation in the PROM1 gene as a causative mutation in two patients with sporadic retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited retinal diseases caused by the loss of photoreceptors. The present study aimed to identify the gene mutations responsible for RP in two patients diagnosed with sporadic RP using next-generation sequencing technology. For this purpose, two patients with sporadic RP and family members (namely parents and siblings) were recruited into this study and underwent a complete ophthalmological assessment. Whole-exome sequencing (WES) was performed on genomic DNA samples isolated from peripheral leukocytes which had been obtained from the two patients diagnosed with sporadic RP. WES data were annotated and filtered against four public databases and one in-house database. Subsequently, Sanger sequencing was performed in order to determine whether any of the candidate variants co-segregated with the disease phenotype in the families. A homozygous frameshift mutation, c.1445dupT (p.F482fs) in exon 12 of the PROM1 gene (MIM: 604365), satisfied a recessive inheritance model and showed complete co-segregation of the mutation with the disease phenotype in the families. The same mutation was not detected in the 200 ethnically-matched control samples by Sanger sequencing. The novel homozygous mutation c.1445dupT (p.F482fs) in the PROM1 gene was identified as a causative mutation for RP. Thus, the identification of this mutation has further expanded the existing spectrum of PROM1 mutations in patients with RP, thereby assisting in the molecular diagnosis of RP and enhancing our understanding of genotype-phenotype correlations in order to provide effective genetic counseling.

Clinical and genetic characteristics of 10 Japanese patients with PROM1‐associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

“…Variants in the PROM1 gene have been associated with CORD/COD, MD, STGD, and RP (Arai et al, 2015; Arrigoni et al, 2011; Beryozkin et al, 2014; Birtel et al, 2018; Boulanger‐Scemama et al, 2015; Carss et al, 2017; Cehajic‐Kapetanovic et al, 2019; Collison et al, 2019; Eidinger et al, 2015; Eisenberger et al, 2013; Imani et al, 2018; Jinda et al, 2014; Khan & Bolz, 2015; Kim et al, 2017, 2019; Kniazeva et al, 1999; Liang et al, 2019; Littink et al, 2010; Liu et al, 2016; Maw et al, 2000; Mayer et al, 2016; Michaelides et al, 2005, 2010; Michaelides, Johnson, et al, 2003; Permanyer et al, 2010; Pras et al, 2009; Ragi et al, 2019; Salles et al, 2017; Song et al, 2011; Strauss et al, 2018; Wawrocka et al, 2018; Yang et al, 2008; Zhang et al, 2007; Zhao et al, 2015). Over 90 disease‐associated PROM1 variants have been identified in AD and AR manners (The Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/ac/index.php) (Supporting Information 1).…”

Recent Developments on the major genes involved in retinitis pigmentosa

“…2,33 Although, there is no absolute linkage between ROM1 mutations and monogenic adRP, 31 there are cases of autosomal digenic RP in patients heterozygous for both a PRPH2 mutation and a ROM1 mutation. 2,6,34 However, there are individuals appearing with ROM1 alterations in the absence of PRPH2 mutations. 13 The appearance of different phenotypes in patients with mutations in the same gene remains under investigation.…”

“…The PROM 1 gene is localized on chromosome 4 (4p15.32), 6,34,68 consists of twenty-seven exons and encodes prominin-1, a five-transmembrane domain glycoprotein 6,34 . Stem and progenitor cells from neural and hematopoietic systems mainly express prominin-1.…”

“…More specifically, PROM1 enhances disk membrane morphogenesis, as it is mostly found at the base of outer segments of photoreceptors. 68 Over 35 mutations of the PROM 1 gene have been identified, 34 most of them implicated in several retinal degenerative phenotypes, like arRP affecting the macula, autosomal dominant Stargardt disease, autosomal dominant macular dystrophies with bull's eye and CRD. 1,69 However, probably there is a relationship between each mutation and the phenotype that is apparent.…”

“…Characteristically, autosomal dominant Stargardt disease and macular dystrophy with bull's eye are associated with missense mutations, while nonsense mutations and frameshift mutations may cause RP, CRD or other forms of macular degeneration. 34,70 There are many arRP cases reported in China and Thailand that are related with PROM1 mutations. 34 while recessive PROM1 mutations have been associated with progressive RP, affecting the macula, in Spanish families.…”