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Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6 - PubMed

  • ️Sat Jan 01 2005

Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6

Thaddeus P Dryja et al. Proc Natl Acad Sci U S A. 2005.

Abstract

We report three unrelated patients with mutations in the GRM6 gene that normally encodes the glutamate receptor mGluR6. This neurotransmitter receptor has been shown previously to be present only in the synapses of the ON bipolar cell dendrites, and it mediates synaptic transmission from rod and cone photoreceptors to this type of second-order neuron. Despite the synaptic defect, best visual acuities were normal or only moderately reduced (20/15 to 20/40). The patients were night blind from an early age, and when maximally dark-adapted, they could perceive lights only with an intensity equal to or slightly dimmer than that normally detected by the cone system (i.e., 2-3 log units above normal). Electroretinograms (ERGs) in response to single brief flashes of light had clearly detectable a-waves, which are derived from photoreceptors, and greatly reduced b-waves, which are derived from the second-order inner retinal neurons. ERGs in response to sawtooth flickering light indicated a markedly reduced ON response and a nearly normal OFF response. There was no subjective delay in the perception of suddenly appearing white vs. black objects on a gray background. These patients exemplify a previously unrecognized, autosomal recessive form of congenital night blindness associated with a negative ERG waveform.

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Figures

Fig. 1.
Fig. 1.

The top portion of this figure shows the DNA sequence chromatograms of the four mutations identified in the GRM6 gene in patients with night blindness. For each mutation displayed, the top chromatogram is the mutant sequence, and the bottom is wild-type sequence. The sequence listed above the chromatograms corresponds with the mutant sequence, with the wild-type base listed below. The wild-type codons are shown above the sequence. The sequence and chromatograms for the mutation Gly-150 → Ser are shown in the antisense direction. The bottom portion of the figure shows the analysis of these mutations in the available relatives of the patients. The number to the top left of each pedigree is the family identifier. The genotype of each patient tested is listed below the patient symbol. The probands are marked with arrows.

Fig. 2.
Fig. 2.

ERGs of a normal control and patients 063-007 at age 17 and 274-021 at age 14 recorded at the Berman-Gund Laboratory at MEEI. The top row shows the dark-adapted rod responses to 0.5-Hz blue light flashes; the second row shows the dark-adapted rod-plus-cone responses to 0.5-Hz bright white light flashes; the third row shows the light-adapted cone responses to 0.5-Hz flashes; and the bottom row shows the cone responses to 30-Hz white light without a background light. In each tracing, two or three sweeps are super-imposed to illustrate reproducibility. In the 0.5-Hz cone response in the normal control (third tracing from the top), an oblique arrow points to an oscillation on the upward slope of the b-wave that is not observed in the patients. (Scale bars: 50 msec horizontally and 100 μV vertically for all tracings.)

Fig. 3.
Fig. 3.

ERGs of a normal control (Left) and patients 274-011 at age 30 (Center) and 063-007 at age 31 (Right) recorded at the UIC. Left shows normal ERG recordings for comparison. The types of recordings from top to bottom are the same as those in Fig. 2, except that the light stimuli are brighter (see Materials and Methods), the flash frequencies are greater (see labels at left), and the 32-Hz cone ERGs (bottom row) were recorded with a background light. In the light-adapted cone response in the normal control (third tracing from the top), an oblique arrow points to one of the two oscillations on the upward slope of the b-wave that is not observed in the patients. (Scale bars: 50 msec horizontally and 100 μV vertically for all tracings.)

Fig. 4.
Fig. 4.

ERGs in response to sawtooth light stimuli. ERGs of a normal control (top traces) and patients 063-007 (middle traces) and 274-011 (bottom traces) in response to rapid-on (Left) and rapid-off (Right) sawtooth stimuli at a frequency of 6.25 Hz. The a-, b-, and d-waves of the control subject are indicated by arrows. The shaded region on the x axis illustrates the stimulus waveform.

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