Autosomal Dominant Retinitis Pigmentosa 17 (RP17) via the CA4 Gene

Retinitis pigmentosa (RP; OMIM # 268000) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42 (11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia ("night blindness"), followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-334, 1999). RP17 (OMIM # 600852) is characterized by the reduction of both rod (scotopic) and cone (photopic and flicker) responses in the electroretinogram (Yang et al. Hum Mol Genet 14(2):255-265, 2005).

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (ad), autosomal recessive (ar) or X-linked (XL) inheritance. To date, over 50 loci have been linked to nonsyndromic RP and 18, 27 and 2 genes have been identified that are associated with adRP, arRP, and XLRP, respectively (RetNet). Carbonic anhydrase 4 (CA4; OMIM # 114760), the adRP gene located on 17q23.1 encodes a glycosylphosphatidylinositol membrane-anchored zinc metalloenzyme (the CAIV protein), which is predominantly expressed in the choriocapillaris of the eye, but not in the retina (Alvarez et al. Invest Ophthalmol Vis Sci 48(8):3459-3468, 2007; Rebello et al. Proc Natl Acad Sci U S A 101(17):6617-6622, 2004; Yang et al., 2005). Retinal phototransduction is highly sensitive to extracellular pH changes. pH homeostasis is maintained by efficient acid removal mediated by choriocapillaris from the retina and retinal pigment epithelium (RPE), which have a high rate of metabolism and consequently a high rate of endogenous acid production. This process requires the functional interaction between CAIV and Na+/bicarbonate co-transporter 1 (NBC1). The CAIV and NBC1 complex is specifically expressed in the choriocapillaris (Alvarez et al. Biochemistry 42(42):12321-9, 2003). So far, about 10 mutations (missense and regulatory variants) in CA4 have been associated with adRP (Human Gene Mutation Database), and these pathogenic mutations have been shown to impair the CAIV and NBC1 interaction. Also, functional analysis of two CA4 mutations (Arg14Trp, Arg219Ser) revealed that they lead to the accumulation of unfolded forms of CAIV in the endoplasmic reticulum (ER) of choriocapillaris endothelial cells, which subsequently activates the unfolded protein response (UPR). The induced UPR leads to chronic ER stress and ultimately apoptosis of these cells and subsequently leads to ischemia of the overlying retina and adRP (Rebello et al., 2004).

Mutational screening in 96 patients with simplex RP and adRP of Chinese ethnicity, identified a CA4 pathogenic mutation (R69H) in 1 patient with simplex RP (~1%), which was not found in 432 normal chromosomes (Alvarez et al. Invest Ophthalmol Vis Sci 48(8):3459-3468, 2007).

So far, no gross deletions or duplications have been reported in CA4 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CA4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).