Mutations in <i>GUCY2D</i>, the gene encoding retinal guanylate cyclase-1 (retGC1), are the leading cause of autosomal dominant cone-rod dystrophy (CORD6).
The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy.
Our study suggested that GUCY2D is a major cause of autosomal dominant cone and cone-rod dystrophies in Israel; this is similar to other Caucasian populations and is in contrast with retinitis pigmentosa (primary rod disease), where the genetic make-up of the Israeli population is distinct from other ethnic groups.
This study hence establishes GUCY2D, which is a common cause for both recessive LCA and dominant cone-rod dystrophy, as a good candidate for autosomal recessive cone-rod dystrophy.
This report gives support to the existence of exceptional GUCY2D mutations accounting for a milder and different phenotype compared to the typical GUCY2D congenital stationary cone-rod dystrophy.
Mutations in the gene coding for photoreceptor specific guanylate cyclase type 1, ROS-GC1, were found to be the cause for the type 1 Leber's congenital amaurosis (LCAI) and cone-rod dystrophy type 6 (CORD6).
The cone and cone-rod dystrophies that are caused by mutations in RetGC1 or GCAP1 arise from a perturbation of the delicate balance of Ca2+ and cGMP within the photoreceptor cells and it is this disruption that is believed to cause cell death.
The phenotype associated with autosomal dominant cone-rod dystrophy with either an R838C or R838H mutation in GUCY2D is distinctive, with predominantly cone system involvement.
Linkage analysis mapped the disease gene in this family to 17p12-p13, a chromosome region previously linked to cone-rod dystrophy in a Swedish family (CORD5).
Three different mutations in codon 838 of GUCY2D, the gene for retinal guanylate cyclase 1, have been linked to autosomal dominant cone-rod dystrophy at the CORD6 locus.
It is worth noting that all retGC1 mutations consistently caused congenital cone-rod dystrophy in our series, confirming the previous genotype-phenotype correlations we were able to establish.
Based on these striking differences of physiopathologic processes, we reexamined all clinical physiopathological discrepancies and the results strongly suggested that retGC1 gene mutations are responsible for congenital stationary severe cone-rod dystrophy, while RPE65 gene mutations are responsible for congenital severe but progressive rod-cone dystrophy.
Two point mutations, E786D and R787C, in ROS-GC1 have been connected with cone-rod dystrophy (CORD6), with only one type of point mutation occurring in each family.
We suggest that the gain-of-function effects of R838C on RetGC-1 stimulated by GCAP-1, which are dominant in vitro and may cause an abnormal increase in cGMP synthesis in dark-adapted photoreceptors, may be the cause of the cone-rod degeneration.
A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy.