Conclusive evidence for a distinct congenital stationary night blindness locus in Xp21.1.

X linked congenital stationary night blindness (CSNBX) is a non-progressive retinal disorder characterised by decreased visual acuity and disturbance of night vision. CSNBX appears to be not only clinically but also genetically heterogeneous. On studying a single large family, we recently suggested the presence of a distinct locus for CSNBX in Xp21.1. Here, we describe the results of a linkage analysis in another large CSNBX family, which confirms this finding. Thus, the data presented here provide conclusive evidence for a distinct CSNBX locus in Xp21.1, closely linked to the X linked retinitis pigmentosa type 3 gene. The results combined with other published results indicate the order Xpter-DXS451-DMD-DYS1-(DXS1110, CSNBX1, XLRP3)-DXS7-(CSNBX2, XLRP2)-DXS14-Xcen.     

Mutations in the CACNA1F and NYX genes in British CSNBX families

X-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX.     

A novel mutation within the rhodopsin gene (Thr‐94‐Ile) causing autosomal dominant congenital stationary night blindness

More than 100 mutations within the rhodopsin gene have been found to be responsible for some forms of retinitis pigmentosa, a progressive retinal degeneration characterized by night blindness and subsequent disturbance of day vision that may eventually result in total blindness. Congenital stationary night blindness (CSNB) is an uncommon inherited retinal dysfunction in which patients complain of night vision difficulties of a nonprogressive nature only and in which generally there is no involvement of day vision. We report the results of molecular genetic analysis of an Irish family segregating an autosomal dominant form of CSNB in which a previously unreported threonine‐to‐isoleucine substitution at codon 94 in the rhodopsin gene was found to segregate with the disease. Computer modeling suggests that constitutive activation of transducin by the altered rhodopsin protein may be a mechanism for disease causation in this family. Only two mutations within the rhodopsin gene have been previously reported in patients with congenital stationary night blindness, constitutive activation also having been proposed as a possible disease mechanism. Hum Mutat 13:75–81, 1999. © 1999 Wiley‐Liss, Inc.     

Complete congenital stationary night blindness maps on Xp11.4 in a Sardinian family.

X-linked congenital stationary night blindness (CSNBX) is a hereditary non-progressive retinal disorder, which can appear in two different clinical forms, complete and incomplete, associated with CSNB1 and CSNB2 loci on Xp. We describe a Sardinian family with complete CSNBX and define better the limits of the CSNB1 genetic locus on Xp11.4 through linkage analysis. Haplotype analysis showed two key recombinants, which restrict the CSNB1 locus to a region of about 3 cM limited by markers DSX1068 and DSX6810 respectively. The locus that we describe is included in the CSNB1 locus defined by previous reports referring to the same clinical form of the disease. These results, in addition to other recent mapping reports about families from different geographical areas, confirm the genetic homogeneity of X-linked complete CSNB.     

Linkage analysis-in a family with complete type congenital stationary night blindness with and without myopia

Dry KL, Van Dorp DB, Aldred MA, Brown J, Hardwick LJ, Wright AF. Linkage analysis in a family with complete type congenital stationary night blindness with and without myopia.
Clin Genet 1993: 43: 250–254. © Munksgaard, 1993
A family is described with X-linked congenital stationary night blindness of the complete type (CSNB1) in which clinical variation between affected males resulted in diagnostic difficulties. In two affected male cousins, one had congenital nystagmus and myopia, while the other was initially thought to have retinitis pigmentosa with optic atrophy and was hyperopic The diagnosis of X-linked congenital stationary night blindness was established by clinical, psychophysical and electrophysiological criteria, and DNA markers flanking the CSNB1 locus were analysed in the family. The results show that both affected males have inherited the same haplotype from their carrier mothers, excluding the possibility that a myopia gene in linkage disequilibrium with CSNB1 has recombined with this locus.     

Novel mutations of the RPGR gene in RP3 families

X-linked retinitis pigmentosa is a severe retinal degeneration characterized by night blindness and visual field constriction, leading to complete blindness within the third decade of life. Mutations in the RPGR gene (retinitis pigmentosa GTPase regulator), located on Xp21.1 in the RP3 region, have been associated with an RP phenotype. Further to our previous mutation screening of RPGR in families segregating with the RP3 locus, we have expanded this study to include other 8 RP3 pedigrees. Here we report the results of this expanded study and the identification of five mutations in RPGR, four of which are novel (IVS6+5 G>A, 950-951delAA, 963 T>C, EX8del) and one of which occurs in the donor splice site of intron 1 (IVS1+1 G>A). These findings bring the proportion of "RP3 genotypes" with a mutation in this gene to 27% (10/37). Hum Mutat 15:386, 2000.     

A novel nonsense variant in REEP6 is involved in a sporadic rod‐cone dystrophy case

Rod‐cone dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60‐year‐old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect.     

Phenotype-genotype correlations in X linked retinitis pigmentosa.

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0).     

Identification of a key recombinant which assigns the incomplete congenital stationary night blindness gene proximal to MAOB.

The gene for complete congenital stationary night blindness (CSNB1) has been assigned to the Xp11.3 region. However, little evidence has been provided for the assignment of the incomplete congenital stationary night blindness gene (CSNB2). Here we present the clinical and molecular data from a CSNB2 family which show a key recombinant assigning the CSNB2 gene proximal to MAOB.     

Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1

Fundus albipunctatus (FA; OMIM 136880) is a rare form of apparently stationary night blindness characterized by the presence of myriad symmetrical round white dots in the fundus with a greater concentration in the midperiphery. A distantly similar but distinct clinical entity, retinitis punctata albescens (RPA), is also characterized by aggregation of irregular white flecks but is progressive and evolves to generalized atrophy of the retina. We studied 4 consanguineous kindreds diagnosed with FA from Saudi Arabia. Given the substantial phenotypic variation and overlap between different flecked retinal dystrophies, we evaluated all known genes associated with such conditions by both genetic analysis and direct sequencing. In one kindred, KKESH-099, we identified a homozygous R150Q alteration in RLBP1, the gene encoding the cellular retinaldehyde binding protein, associated previously with both recessive retinitis pigmentosa (arRP) and RPA. Examination of several patients aged 3-20 years over a 9-year period presented no evidence for either RP or RPA. In contrast, clinical examination of individuals with the same mutation in their fourth and fifth decade revealed signs consistent with RPA. The data suggest that the R150Q mutation in RLBP1 may result in RPA with slow progression. More importantly, younger individuals diagnosed with the milder disorder FA thought to be stationary may evolve to a more devastating and progressive phenotype.     

A patient homozygous for the SCA6 gene with retinitis pigmentosa

The present authors studied a 55-year-old-patient homozygous for the SCA6 gene who experienced frequent attacks of positional vertigo at 37 years of age with subsequent staggering gait and night blindness. Retinitis pigmentosa (RP), as well as cerebellar ataxia and vertical antidirectional nystagmus, were detected. The subject's parents were first cousins, and two of his three male cousins, whose parents were also first cousins, had RP without ataxia or nystagmus. The numbers of CAG repeats in the expanded alleles of the SCA6 gene found by molecular analysis were 21 and 21. The genetic results were negative for SCA1, SCA2, SCA3, SCA7 and dentatorubral pallidoluysian atrophy. The retinal degeneration in this patient is most likely to be secondary to a genetic disorder of autosomal or X-linked recessive inheritance rather than SCA6. Other reported cases of patients homozygous for the SCA6 gene are also reviewed.     

Retinal horizontal cells reduced in a rat model of congenital stationary night blindness

This work was conducted to determine whether congenital stationary night blindness (CSNB), which is caused by a Cacna1f mutation, could affect development of second-order neurons in the retina, such as horizontal cells (HCs). The CSNB rats and age-matched wild type rats were sacrificed at postnatal days (PND) 15, 30 and 60. Morphometric analyses of HCs, which were labeled by a primary antibody to calbindin D-28K, were performed at the light microscopic level on retinal cross sections and whole mount retinas. Calbindin D-28K was measured by western blotting in retinal samples. We found that the average number and density of HCs, Calbindin level and thickness of OPL were all decreased significantly in CSNB group compared to control group. These results indicated that second-order retinal neurons, such as horizontal cells, are affected by retinal degeneration. The relationship between the absence of HCs and the gene defect of CSNB requires further research.     

Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa

BACKGROUND. Night blindness is an early symptom of retinitis pigmentosa. The rod photoreceptors are responsible for night vision and use rhodopsin as the photosensitive pigment. METHODS AND RESULTS. We found three mutations in the human rhodopsin gene; each occurred exclusively in the affected members of some families with autosomal dominant retinitis pigmentosa. Two mutations were C-to-T transitions involving separate nucleotides of codon 347; the third was a C-to-G transversion in codon 58. Each mutation corresponded to a change in one amino acid residue in the rhodopsin molecule. None of these mutations were found in 106 unrelated normal subjects who served as controls. When the incidence of these three mutations was added to that of a previously reported mutation involving codon 23, 27 of 150 unrelated patients with autosomal dominant retinitis pigmentosa (18 percent) were found to carry one of these four defects in the rhodopsin gene. All 27 patients had abnormal rod function on monitoring of their electroretinograms. It appears that patients with the mutation involving codon 23 probably descend from a single ancestor. CONCLUSIONS. In some patients with autosomal dominant retinitis pigmentosa, the disease is caused by one of a variety of mutations of the rhodopsin gene.     

Duchenne muscular dystrophy: negative electroretinograms and normal dark adaptation. Reappraisal of assignment of X linked incomplete congenital stationary night blindness.

Aland Island eye disease (AIED) and X linked congenital stationary night blindness (CSNB) have been mapped to Xp11.3. Patients have been described with deletions of the Duchenne muscular dystrophy (DMD) gene who also had a negative electroretinogram (ERG) similar to that seen in patients with CSNB and AIED. This seems to confirm that some cases of AIED and CSNB map to Xp21. We examined 16 boys with DMD/BMD (Becker muscular dystrophy) of whom 10 had negative ERGs, eight of them having deletions downstream from exon 44. Normal dark adaptation thresholds were observed in all patients and there were no anomalous visual functions. Hence, CSNB cannot be assigned to Xp21 and negative ERG in DMD/BMD is not associated with eye disease. Six boys with DMD/BMD had normal ERGs. We speculate that a retinal or glial dystrophin may be truncated or absent in the boys with negative ERGs.     

Species specific membrane anchoring of nyctalopin, a small leucine-rich repeat protein

Mutations in the gene NYX, which encodes nyctalopin, lead to the retinal disorder congenital stationary night blindness which is characterized by defective night vision (nyctalopia) from birth. Nyctalopin is of unknown function but is predicted to be a secreted glycoprotein of the extracellular small leucine-rich repeat (SLRP) proteoglycan and protein family attached to the cell membrane in humans via a glycosylphosphatidylinositol (GPI) anchor but in mouse via a transmembrane domain. We investigated membrane association and attachment for human and mouse nyctalopin and show, conclusively, that human nyctalopin is a GPI anchored protein. In addition, the orthologous mouse protein, although it localizes to the cell surface, is not GPI anchored. We also confirm both mouse and human nyctalopins are glycosylated. Further sequence analysis suggests that chimp, dog and frog nyctalopins are likely to be GPI anchored but that rat nyctalopin is not. This is the first reported example of orthologous proteins which have different mechanisms of cell membrane attachment. Notably, the disease-causing mutations that have been identified to date in the human NYX gene are all distributed throughout the core LRR region and not in the C-terminal GPI anchor signal sequence. We propose that the presence of nyctalopin on the surface of the cell rather than the mechanism of anchoring is crucial to its function.     

Prevalence of AIPL1 mutations in inherited retinal degenerative disease

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy and the most frequent cause of inherited blindness in children. LCA is usually inherited in an autosomal recessive fashion, although rare dominant cases have been reported. One form of LCA, LCA4, maps to chromosome 17p13 and is genetically distinct from other forms of LCA. We recently identified the gene associated with LCA4, AIPL1 (aryl-hydrocarbon interacting protein-like 1) and identified three mutations that were the cause of blindness in five families with LCA. In this study, AIPL1 was screened for mutations in 512 unrelated probands with a range of retinal degenerative diseases to determine if AIPL1 mutations cause other forms of inherited retinal degeneration and to determine the relative contribution of AIPL1 mutations to inherited retinal disorders in populations worldwide. We identified 11 LCA families whose retinal disorder is caused by homozygous or compound heterozygous AIPL1 mutations. We also identified affected individuals in two apparently dominant families, diagnosed with juvenile retinitis pigmentosa or dominant cone-rod dystrophy, respectively, who are heterozygous for a 12-bp AIPL1 deletion. Our results suggest that AIPL1 mutations cause approximately 7% of LCA worldwide and may cause dominant retinopathy.     

Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa

Retinitis pigmentosa (RP) is a common hereditary eye disease that causes blindness due to a progressive loss of photoreceptors in the retina. RP can be elicited by mutations that affect the tri-snRNP subunit of the pre-mRNA splicing machinery, but how defects in this essential macromolecular complex transform into a photoreceptor-specific phenotype is unknown. We have modeled the disease in zebrafish by silencing the RP-associated splicing factor Prpf31 and observed detrimental effects on visual function and photoreceptor morphology. Despite reducing the level of a constitutive splicing factor, no general defects in gene expression were found. Instead, retinal genes were selectively affected, providing the first in vivo link between mutations in splicing factors and the RP phenotype. Silencing of Prpf4, a splicing factor hitherto unrelated to RP, evoked the same defects in vision, photoreceptor morphology and retinal gene expression. Hence, various routes affecting the tri-snRNP can elicit tissue-specific gene expression defects and lead to the RP phenotype.