Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy

Abstract

he gene GUCA1A (OMIM *600364) encodes the protein guanylate cyclase activating protein-1, a calciumsensitive protein integral to maintaining cyclic guanosine monophosphate levels in the outer segment of photoreceptors. Variants in this gene may be associated with a dominantly inherited cone dystrophy, largely by affecting calcium sensitivity. 1-4 In 2001, 3 families with variants in GUCA1A were reported in this journal. 2 Two families had the p.(Tyr99Cys) variant, with a relatively consistent phenotype. The third family had the p.(Pro50Leu) variant and exhibited a more variable phenotype (the proband had a cone dystrophy, but an affected relative had features consistent with retinitis pigmentosa). Since that publication, this family has undergone more detailed investigation, the results of which are described in the present report; we now associate their phenotype with a disease-causing variant in RPGR (OMIM *312610, coding for the retinitis pigmentosa [RP] GTPase regulator protein, thought to facilitate protein trafficking in photoreceptors) and not GUCA1A. Two of us (S.M.D. and A.B.) were also contributing authors of the original report. 2 Methods Clinical Examination and Imaging This study was performed from October 27, 2009, to May 23, 2019, after the original evaluation of the family, because the proband's daughter underwent a fundus examination (see Results). A fundal examination was performed at the slitlamp after mydriasis, and color fundus images and redfree images were taken from both eyes. The study was approved by Moorfields Eye Hospital and Northwest London Research Ethics Committee, and conformed to the tenets of the Declaration of Helsinki. 5 Participants provided written informed consent. IMPORTANCE As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance. OBJECTIVE To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the gene GUCA1A was associated with a dominant retinal dystrophy, in light of new examination findings in the proband's daughter. DESIGN, SETTING, AND PARTICIPANTS A genetic study relating to a family with an inherited retinal dystrophy was performed at the retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband's daughter underwent fundus examination. MAIN OUTCOMES AND MEASURES Results of sequencing of X chromosome-linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of the RPGR gene. RESULTS A frame-shifting single-nucleotide deletion was found in the ORF15 exon of RPGR (GRCh37 [hg19] x:38145160delT; NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant in GUCA1A was also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant retinal dystrophy. CONCLUSIONS AND RELEVANCE The phenoty...

Dominant Cone Rod Dystrophy, Previously Assigned to a Missense Variant in RIMS1, Is Fully Explained by Co-Inheritance of a Dominant Allele of PROM1

“…In order to fully refute false attributions of pathogenicity to particular genetic variants, it is important to identify the correct pathogenic variant in the original cases. 1 – 3 …”

Update to Open Access Status

“…In the Brief Report titled “Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy,” published in the February issue of JAMA Ophthalmology , the authors updated the status of the article so that it is now Open Access. This article has been corrected online.…”