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.     

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.     

Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness

Mutations in the NYX gene that encodes the protein nyctalopin cause congenital stationary night blindness type 1. In no b-wave (nob) mice, a mutation in Nyx results in a functional phenotype that includes the absence of the electroretinogram b-wave and abnormal spontaneous and light-evoked activity in retinal ganglion cells (RGCs). In contrast, there is no morphological abnormality in the retina at either the light or electron microscopic levels. These functional deficits suggest that nyctalopin is required for normal synaptic transmission between retinal photoreceptors and depolarizing bipolar cells (DBCs). However, the synaptic etiology and, specifically, the exact location and function of nyctalopin, remain uncertain. We show that nob DBCs fail to respond to exogenous application of the photoreceptor neurotransmitter, glutamate, thus demonstrating a postsynaptic deficit in photoreceptor to bipolar cell communication. To determine if postsynaptic expression of nyctalopin is necessary and sufficient to rescue the nob phenotype, we constructed transgenic mice that expressed an EYFP-nyctalopin fusion protein on the dendritic tips of the DBCs. Immunohistochemical and ultrastructural studies verified that fusion protein expression was limited to the DBC dendritic tips. Fusion gene expression in nob mice restored normal outer and inner visual function as determined by the electroretinogram and RGC spontaneous and evoked responses. Together, our data show that nyctalopin expression on DBC dendrites is required for normal function of the murine retina.     

Localization of a novel X-linked congenital stationary night blindness locus: close linkage to the RP3 type retinitis pigmentosa gene region

X-linked congenital stationary night blindness (CSNBX) is anon-progressive retinal disorder characterized by decreasedvisual acuity and loss of night vision. CSNBX Is clinicallyheterogeneous with respect to the involvement of retinal rodsand/or cones in the disease. in this study, we localize a newlocus for CSNBX to Xp21.1, thus providing evidence that CSNBXis also genetically heterogeneous. A clear correlation betweendifferent genotypes and phenotypes cannot be found yet. Thenew CSNBX gene described here is closely linked to the X-linkedretinitis pigmentosa type 3 gene region, which supports thehypothesis that there may be a functional relationship betweencongenital stationary night blindness and retinitis pigmentosa.     

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.     

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

The contribution of angiotensin II (Ang II) to the pathophysiology of hypertension is established based on facts that high levels of circulating Ang II increase vasoconstriction of peripheral arteries causing a rise in blood pressure (BP). In addition, circulating Ang II has various effects on the central nervous system, including the osmosensitive neurons in the organum vasculosum of the lamina terminalis (OVLT). Osmosensitive neurons in the OVLT transduce hypertonicity via the activation of the nonselective cation channel known as transient receptor potential vanilloid 1 (TRPV1), causing membrane depolarization, followed by increased action potential discharge. This effect is absent in mice lacking expression of the TRPV1 gene. Most observations related to the importance of the OVLT in cardiovascular control are mainly based on models of lesion of the entire preoptic periventricular tissue. However, it remains unclear whether neuronal activity and TRPV1 protein expression levels alter in the OVLT of Cyp1a1-Ren2 transgenic rats with inducible Ang II-dependent malignant hypertension. C-fos was used as a marker of neuronal activity. Immunostaining was used to demonstrate distribution of c-fos positive neurons in the OVLT of Cyp1a1Ren2 transgenic rats. Western blot analysis showed increased c-fos and TRPV1 total protein expression levels in the OVLT of hypertensive rats. The present findings demonstrate increased c-fos and TRPV1 expression levels in the OVLT of Cyp1a1-Ren2 transgenic rats with Ang II-dependent malignant hypertension.     

Multifocal oscillatory potentials in CSNB1 and CSNB2 type congenital stationary night blindness

We evaluated the function of the inner retina in patients with congenital stationary night blindness of the complete (CSNB1) and the incomplete type (CSNB2) by recording multifocal oscillatory potentials (mf-OPs). The VERIS system was used to record mf-OPs from 61 areas of the central retina from 5 CSNB1 patients (4 with NYX gene mutation), 6 CSNB2 patients (2 with CACNA1F mutation) and 11 control subjects. For each subject group, the first- and second-order kernel responses for one eye were analysed and the amplitudes and implicit times of their major components compared to 5 concentric rings centred on the fovea. In CSNB1 patients, the mf-OP peak amplitudes of the first-order kernel responses showed a significant reduction of the first peak without significant reduction of the second, whereas in CSNB2 both peak amplitudes were barely discernable from noise for all eccentricities. In the second-order kernel, the third peak was reduced in CSNB1 patients, and again not discernable from noise in CSNB2 patients. The difference in amplitude between the control and CSNB1 groups was significant for the late components of the first- and the second-order kernel. Implicit times were not significantly altered. The difference in mf-OP amplitude between CSNB1 and CSNB2 patients reflects the different molecular mechanisms underlying the two types of disease, which differentially affect the postreceptoral pathways of cone signal processing. The well-preserved peak 2 amplitudes of first-order mf-OPs and peak 3 amplitudes of second-order mf-OPs in CSNB1 patients point to a major impact of OFF-pathway components on these responses which are not present in CSNB2 patients. In conclusion, our results show that CSNB1 and CSNB2 are two different types of disease, not only on a genetic but also on a pathophysiological level.     

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.     

一个先天性静止性夜盲症家系致病基因的突变分析

目的 检测和分析河南1个常染色体显性先天性静止性夜盲症( autosomal dominant congenital stationary night blindness,ADCSNB)家系相关基因的致病突变.方法 从该家系14名成员的外周血提取基因组DNA,根据已报道的ADCSNB的3个致病基因的6个相关位点设计引物.利用PCR扩增相关位点所在的外显子,纯化扩增产物后进行正反向测序.结果 在该家系患者的RHO基因中发现了1个c.281C＞T的杂合错义点突变,该突变在蛋白质水平将导致p.Thr94Ile的改变,而在该家系正常成员以及50名正常对照中未发现此突变.结论 RHO基因c.281C＞T突变(p.Thr94Ile)为该家系先天性静止性夜盲症发病的分子遗传学基础.     

Opsin activation as a cause of congenital night blindness

Three different mutations of rhodopsin are known to cause autosomal dominant congenital night blindness in humans. Although the mutations have been studied for 10 years, the molecular mechanism of the disease is still a subject of controversy. We show here, using a transgenic Xenopus laevis model, that the photoreceptor cell desensitization that is a hallmark of the disease results from persistent signaling by constitutively active mutant opsins.     

Congenital stationary night blindness: report of an autosomal recessive family and linkage analysis

Congenital stationary night blindness (CSNB) is a group of rare, non-progressive conditions of the retina characterized by abnormal rod function causing impaired night vision. Among them, the Schubert-Bornschein subgroup, itself divided into a complete and an incomplete form, is characterized by a specific electrophysiological pattern. Complete, Schubert-Bornschein CSNB is usually transmitted as a monogenic trait, and most familial cases result from mutations of the NYX gene located on the X chromosome. We report a very rare family with consanguineous, first-cousin parents, where a son and a daughter are affected with this condition, indicating autosomal recessive inheritance. As the family was too small for genome-wide linkage, we considered several candidate loci, including the sidekick SDK1 and SDK2 genes. The latter determine lamina-specific connectivity in the retina, a histological substrate of the ON pathway implicated in complete, Schubert-Bornschein CSNB. Although linkage was excluded in our family, observations like the present one may lead to the identification of a new molecular cause for this condition.     

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.     

X-linked spastic paraplegia: evidence for homogeneity with a variable phenotype

Hereditary spastic paraplegia (HSP) is rarely inherited in an X-linked recessive mode in pure and complicated forms. Recently, molecular linkage studies have suggested that these variant X-linked HSP conditions result from locus heterogeneity. In this paper we report on the clinical and linkage analysis of a kindred with complicated X-linked HSP. The finding in this family of a map location of the putative HSP gene in the same region as the documented for the pure HSP gene provides evidence that allelic mutations might also be responsible for the variable phenotype encountered in these X-linked disorders.     

X-linked congenital ataxia: a clinical and genetic study

We report on a family in which two males are affected with X-linked congenital ataxia (XCA). Clinical manifestations include severe hypotonia at birth, delay of early motor development, slow eye movements, and nonprogressive cerebellar ataxia. The neurological examination excluded a neuromuscular disease, mental retardation, and pyramidal tract involvement. Neuroimaging showed global cerebellar atrophy in both patients that was not evident in the first years of life. The clinical findings in this family are very similar to those in a Russian pedigree [Illarioskin et al., 1996: Ann Neurol 40:75-83] and outline a recognizable phenotype. Linkage studies in our family, using 28 highly polymorphic Généthon microsatellite markers evenly distributed along the X chromosome, excluded a 24 cM interval between DXS990 and DXS424 located within the previous candidate region of 54 cM, reducing the critical interval.     

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.     

Mutation screening of TRPM1, GRM6, NYX and CACNA1F genes in patients with congenital stationary night blindness

The aim of this study was to identify mutations in the TRPM1, GRM6, NYX and CACNA1F genes in patients with congenital stationary night blindness (CSNB). Twenty-four unrelated patients with CSNB were ascertained. Sanger sequencing was used to analyze the coding exons and adjacent intronic regions of TRPM1, GRM6, NYX and CACNA1F. Six mutations were identified in six unrelated patients, including five novel and one known. Of the six, three novel hemizygous mutations, c.92G>A (p.Cys31Tyr), c.149G>C (p.Ary50Pro), and c.[272T>A;1429G>C] (p.[Leu91Gln;Gly477Arg]), were found in NYX in three patients, respectively. A novel c.[1984_1986delCTC;3001G>A] (p.[Leu662del;Gly1001Arg]) mutation was detected in CACNA1F in one patient. One novel and one known heterozygous variation, c.1267T>C (p.Cys423Arg) and c.1537G>A (p.Val513Met), were detected in GRM6 in two patients, respectively. No variations were found in TRPM1. The results expand the mutation spectrum of NYX, CACNA1F and GRM6. They also suggest that NYX mutations are a common cause of CSNB.