Night Blindness, Congenital Stationary, Type 1c

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

RHO, GRM6, TRPM1, GNAT1, LRIT3, SLC24A1, PDE6B, GPR179, SAG, CACNA1F, NYX, CABP4, GNB3, CACNA2D4, GRK1, RDH5, RBP4, TRAPPC9, USH2A, ABCA4, RPGR, RBP3, FGFR2, ERG, GRK7, RPE65, USP11, SOCS2, BBS1, GNAZ

Drugs

Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins

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A number sign (#) is used with this entry because of evidence that autosomal recessive complete congenital stationary night blindness-1C can be caused by homozygous or compound heterozygous mutation in the TRPM1 gene (603576) on chromosome 15q13-q14.

For a general phenotypic description and a discussion of genetic heterogeneity of congenital stationary night blindness, see CSNB1A (310500).

Clinical Features

Li et al. (2009) studied 3 families with complete congenital stationary night blindness (CSNB), 1 of South Asian ethnicity and 2 of Caucasian European descent, in which affected members had myopia, reduced central vision, nystagmus, and electroretinographic (ERG) evidence of ON bipolar cell dysfunction typical of complete CSNB. None had abnormalities of skin pigmentation, although other skin conditions were reported, including dry skin requiring emollients, a history of treatment for 'eczema,' and an uncharacterized condition 'similar to epidermolysis bullosa simplex.'

Mapping

In a consanguineous family of South Asian ethnicity with complete CSNB, Li et al. (2009) performed genomewide linkage analysis and identified a 15.9-Mb candidate region on proximal chromosome 15q, flanked by the polymorphisms rs2090622 and rs10518928.

Molecular Genetics

In a consanguineous family of South Asian ethnicity with complete CSNB, Li et al. (2009) identified homozygosity for a splice site mutation (603576.0001) in the TRPM1 gene in the affected mother; the father was heterozygous for the mutation. Li et al. (2009) screened the TRPM1 gene in 9 families that were negative for mutation in the NYX (300278) and GRM6 (604096) genes and identified compound heterozygosity for TRPM1 mutations in 2 families of Caucasian European descent (see, e.g., 603576.0002-603576.0003). None of the mutations were found in 192 control individuals. Li et al. (2009) noted that in their study, 7 CSNB families had no mutations in the NYX, GRM6, or TRPM1 genes, indicating possible further genetic heterogeneity.

Audo et al. (2009) analyzed the TRPM1 gene in 38 clinically diagnosed CSNB patients and identified homozygosity or compound heterozygosity for 14 causative mutations in 10 unrelated patients, including missense, splice site, deletion, and nonsense mutations (see, e.g., 603576.0004-603576.0005).

In 6 of 8 female probands of European ancestry with complete CSNB, who were negative for mutation in GRM6 and NYX, van Genderen et al. (2009) identified mutations in TRPM1 (see, e.g., 603576.0005-603576.0007). The authors noted that the ERG responses of all 6 TRPM1 probands were identical to those of CSNB patients with NYX mutations, i.e., responses at low intensities were completely absent, whereas they were similar to normal responses at higher intensities, revealing the complete absence of the primary rod pathway and mildly reduced activity of the secondary rod pathway. CSNB patients with mutations in the GRM6 gene (CSNB1B; 257270), however, had been shown to have responses at all intensities that were markedly dissimilar in phase compared to normal responses (Zeitz et al., 2005); van Genderen et al. (2009) concluded that detailed ERG analysis is an effective way to discriminate among patients with mutations in TRPM1 and GRM6.

Nakamura et al. (2010) analyzed the TRPM1 gene in 4 unrelated Japanese patients with CSNB who were known to be negative for mutation in the NYX and GRM6 genes, and identified compound heterozygosity for 5 different mutations in 3 patients (see, e.g., 603576.0008-603576.0010). Fundus examination of the patients, who had night blindness from early childhood, revealed no abnormalities other than myopic changes; the single bright-flash, mixed rod-cone ERG showed a negative-type configuration, with a reduced normal a-wave and a significantly reduced b-wave.

Animal Model

Witzel et al. (1978) described ERG studies in nyctalopic Appaloosa horses which showed photopic and scotopic abnormalities similar to those in humans with congenital stationary night blindness (CSNB) of the Schubert-Bornschein type. Photopic abnormalities consisted of reduced b-wave amplitudes and slower-than-normal b-wave implicit time; dark-adapted ERGs showed a simple negative potential, with a nonrecordable scotopic b-wave but a normal c-wave. Histologic studies revealed no structural abnormalities to account for the functional defect.

The Appaloosa coat spotting pattern in horses is caused by a single incomplete dominant gene, designated 'LP,' homozygosity for which is directly associated with CSNB in Appaloosa horses. Bellone et al. (2008) analyzed the relative expression of 5 candidate genes located in the 6-cM LP region on horse chromosome 1 and found markedly reduced expression of TRPM1 in the retina and pigmented and unpigmented skin of homozygous LP/LP Appaloosa horses compared to non-Appaloosa lp/lp horses (p = 0.001 for all). Bellone et al. (2008) concluded that decreased expression of TRPM1 in the eye and skin might alter bipolar cell signaling as well as melanocyte function, thus causing both CSNB and LP in horses.