Clinical Characteristics And Molecular Pathology Of Nine Patients With Autosomal Recessive Complete Congenital Stationary Night Blindness Due To GRM6 Mutation

Abstract

Purpose: : Changes in photoreceptor glutamate release rate induce bipolar cell responses. Glutamate is detected by metabotropic and ionotropic receptors located in the ON and OFF bipolar cell dendrites respectively. Recessive mutations in the gene encoding the ON bipolar metabotropic glutamate receptor (GRM6) have been associated with complete congenital stationary night blindness (cCSNB).¹ The aim of this study is to report novel mutational data and describe phenotypic variability in GRM6-related retinopathy.

Methods: : Nine patients from seven families (age range 6 to 76; median 10 years) were ascertained in Moorfields Eye Hospital. Clinical examination, imaging, and electrophysiological assessment were performed. The coding region and intron-exon boundaries of GRM6 were sequenced.

Results: : Nine mutations in GRM6 were detected in the seven families studied; eight of these changes are novel. Five missense (p.Gly275Asp, p.Arg352Cys, p.Arg677Cys, p.Arg677His, p.Gly756Asp), two nonsense mutations (p.Gln708X¹, p.Arg238X) and two one base pair deletions (p.Val193fsX15, p.Pro689fsX24) were identified. The median visual acuity for the cohort was 0.2 logMAR (range 0.0 to 2.3). All patients had myopic astigmatism with the median spherical equivalent refraction being -5.9 dioptres (range -0.43 to -17.5). Fundoscopy was within normal limits in 15 eyes and revealed signs of severe myopic maculopathy in three eyes. All patients had electronegative dark-adapted bright flash ERGs consistent with dysfunction occurring post-phototransduction. ON-OFF ERGs and S-cone ERGs showed generalised cone ON system dysfunction in all five patients tested. In the two oldest subjects (aged 76 and 58 years), there was additional rod and cone photoreceptor dysfunction in keeping with myopic degeneration. Pattern ERG P50 was subnormal (N=2) or undetectable (N=2).

Conclusions: : The present report is the largest series of patients with recessive cCSNB due to GRM6 mutation (prior to this study 11 mutations in 12 patients have been described). Presentation can be variable and myopic degeneration may influence the phenotype. Further detailed evaluation and comparison of patients with defects in GRM6 to those with mutations in other genes causing recessive cCSNB (TRPM1, NYX) will help to elucidate the signal processing of the human retina.¹Dryja TP et al. PNAS USA. 2005;102:4884-9

Keywords: inner retina dysfunction: hereditary • electroretinography: clinical • retinal degenerations: hereditary