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Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL

Dec 12, 2020

Downes SM, Nguyen T, Tai V, Broadgate S, Shah M, Al-Khuzaei S, MacLaren RE, Shanks M, Clouston P, Halford S. | Genes (Basel) | 2020 Dec 12 | 11(12) | page 1497 | doi: 10.3390/genes11121497


Abstract

Autosomal recessive retinitis pigmentosa is caused by mutations in over 40 genes, one of which is the ceramide kinase-like gene (CERKL). We present a case series of six patients from six unrelated families diagnosed with inherited retinal dystrophies (IRD) and with two variants in CERKL recruited from a multi-ethnic British population. A retrospective review of clinical data in these patients was performed and included colour fundus photography, fundus autofluorescence (AF) imaging, spectral domain–optical coherence tomography (SD–OCT), visual fields and electroretinogram (ERG) assessment where available. Three female and three male patients were included. Age at onset ranged from 7 years old to 45 years, with three presenting in their 20s and two presenting in their 40s. All but one had central visual loss as one of their main presenting symptoms. Four patients had features of retinitis pigmentosa with significant variation in severity and extent of disease, and two patients had no pigment deposition with only macular involvement clinically. Seven variants in CERKL were identified, of which three are novel. The inherited retinopathies associated with the CERKL gene vary in age at presentation and in degree of severity, but generally are characterised by a central visual impairment early on.


1. Introduction

Inherited retinal dystrophies (IRD) are a heterogeneous group of disorders associated with the dysfunction or death of photoreceptors, resulting in varying severity of visual loss. IRD has an incidence of 1 in 2000–3000, affecting an estimated two million people worldwide [1]. Retinitis pigmentosa (RP; Mendelian Inheritance in Man (MIM) #268000) is the most common IRD, affecting approximately 1 in 4000 people [2], characterised by symptoms of nyctalopia, peripheral visual field loss with a clinical appearance of intraretinal bone spicule pigmentation, pale discs and attenuated vasculature. RP is associated with significant genotypic and phenotypic heterogeneity, with 41 genes described in association with the autosomal recessive form to date (RetNet: https://sph.uth.edu/retnet/accessed 1 July 2020). In 1998, an RP locus (RP26) was mapped to an 11 cM region on chromosome 2q31–32 in a consanguineous Spanish family by Bayes and colleagues [3]. Subsequently, Tuson and colleagues identified a novel gene from the region that was expressed in the retina, named ceramide kinase-like (CERKL) [4]. The coding exons of CERKL were sequenced in the original RP26 family, and all patients were found to be homozygous for a nonsense mutation c.769C > T, p.Arg257* (now annotated as c.847C > T, p.Arg283*, using the numbering based on transcript NM_001030311, which consists of 14 exons) [4]. A further unrelated Spanish family was also identified with the same homozygous change [4].


CERKL shares 29% identity (50% similarity) with the ceramide kinase (CERK) protein, which phosphorylates ceramide to ceramide 1-phosphate, a sphingolipid metabolite which is involved in proliferation, apoptosis, phagocytosis and inflammation [5]. As yet, no kinase activity is reported for CERKL and its function remains unclear [6,7].


The CERKL gene is composed of 14 exons but alternative splicing produces multiple transcripts (Figure 1) [8,9]. Most of the previous studies examining variants in CERKL used isoform NM_201548, but this only contains 13 exons and is missing exon 5. Table 1 lists all the previously published mutations and the novel changes described in the patients in the present study, using NM_001030311 (which consists of 14 coding exons) as the reference. To date, 39 different mutations in CERKL have been identified (see Figure 1 and Table 1 for summary). The majority of these CERKL-associated IRD studies are case reports and many include the results from next-generation sequencing (NGS) testing with minimal phenotype data. There are, however, four studies reporting on at least four families, but these pertain to one ethnicity only in each study (Yemenite Jewish, Spanish, Tunisian and Finnish) [10,11,12,13]. In these reported populations, CERKL is a significant gene contributing to autosomal recessive RP; presumably due to a founder mutation effect.


 

References

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