Biomedical subjects

B Wissinger

Publications and source records attributed to B Wissinger.

At least 19 recordsLinked to original sources

PubMed2005

Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa.

AIM: To identify novel or rare rhodopsin gene mutations in patients with autosomal dominant retinitis pigmentosa and description of their clinical phenotype. METHODS: The complete rhodopsin gene was screened for mutations by DNA sequencing in index patients. Mutation specific assays were used for segregation analysis and screening for controls. Eight patients from five families and their relatives were diagnosed with autosomal dominant retinitis pigmentosa (adRP) by means of clinical evaluation. RESULTS: Mutation screening identified five different rhodopsin mutations including three novel mutations: Ser176Phe, Arg314fs16, and Val20Gly and two missense mutations, Pro215Leu and Thr289Pro, that were only reported once in a mutation report. Electrophysiological and psychophysical testings provide evidence of an impaired rod system with additionally affected cone system in subjects from each genotype group. Visual function tended to be less affected in subjects with the Arg314fs16 and Val20Gly mutations than in the Ser176Phe phenotype. In contrast, Pro215Leu and Thr289Pro mutations caused a remarkably severe phenotype. CONCLUSION: The ophthalmic findings support a correlation between disease expression and structural alteration: (1) extracellular/intradiscal Val20Gly and cytoplasmic Arg314fs16 mutation-mild adRP phenotype; (2) Ser176Phe mutation-"mostly type 1" disease; (3) predicted alteration of transmembrane domains TM V and TM VII induced by Pro215Leu and Thr289Pro-severe phenotype. However, variation of phenotype expression in identical genotypes may still be a typical feature of RHO mutations.

Adolescent↗

PubMed2004

[Molecular genetic findings in patients with congenital cone dysfunction. Mutations in the CNGA3, CNGB3, or GNAT2 genes].

PURPOSE: This study compares clinical and molecular genetic findings in patients with congenital cone dysfunction. METHODS: In this study 28 patients underwent a basic ophthalmologic examination. Except for a 1-year-old boy, color vision, perimetry, and full-field ERG (ISCEV standard) were evaluated in all patients. Blood samples were taken for molecular genetic analysis of the CNGA3, CNGB3, or GNAT2 genes. RESULTS: Two patient groups could be distinguished: patients without and with residual cone function in the ERG. In 14 of 17 patients without cone function, mutations in one of the three genes were detected, and except for one patient mutations in both alleles could be determined. In these patients, visual acuity was reduced to 20/400 and color discrimination was absent. In 2 of 11 patients with residual cone function, mutations in one allele of the CNGB3 gene were detected. It is of interest that 6 of 16 patients with mutations perceived their disease as progressive; in three of them we could determine a progression. Only in 4 of 16 patients was the ocular fundus normal. The other patients with mutations presented with central pigment irregularities, attenuated vessels, or pale optic disk. CONCLUSION: In patients with congenital cone dysfunction without cone function in the ERG, an analysis of the CNGA3, CNGB3, or GNAT2 gene is advisable. In contrast, patients with residual cone function did not show clear association with mutations in one of the three genes. In patients with mutations, retinal alterations and nystagmus are frequent. In contrast to the designation of these disorders as stationary, in some patients with mutations in the CNGA3 and CNGB3 gene slow progression was observed.

Adolescent↗

PubMed2002

M-cone opsin gene number does not correlate with variation in L/M-cone sensitivity.

Molecular genetic studies demonstrate that the human cone opsin gene array on the q-arm of the X-chromosome typically consists of one long-wave-sensitive (L) cone opsin gene and from one to several middle-wave-sensitive (M) cone opsin genes. Although the presence of the single L-cone opsin gene and at least one M-cone opsin gene is essential for normal red-green colour discrimination, the function of the additional M-cone opsin genes is still unclear. To investigate whether any variations in phenotype correlate with differences in the number of M-cone opsin genes, we selected 13 normal trichromat males, for whom four independent molecular techniques have exactly determined their number of M-cone opsin genes, ranging from one to four. Their phenotype was characterized by estimating their foveal L- to M-cone ratio from heterochromatic flicker photometric (HFP) thresholds, by measuring the wavelength corresponding to their 'unique yellow', and by determining their L- and M-cone modulation thresholds (CMTs). No correlation was found between these psychophysical measures and the number of M-cone opsin genes. Although, we found a reasonably good correlation between the L/M-cone ratios based on HFP and on CMT, we did not find any correlation between the estimated L/M-cone ratios and the settings of 'unique yellow'. Our results accord with previous molecular genetic studies that suggest that only the first two genes in the X-linked opsin gene array are expressed.

Color Perception↗

PubMed2002

A novel mutation of the RP1 gene (Lys778ter) associated with autosomal dominant retinitis pigmentosa.

BACKGROUND: Besides the three known genes (RHO, RDS/Peripherin, NRL) involved in autosomal dominant retinitis pigmentosa (adRP), a fourth gene, RP1, has been recently identified. Initial reports suggest that mutations in the RP1 gene are the second most frequent cause of adRP. The clinical findings were described in a family with adRP and a novel mutation in the RP1 gene. METHOD: Index patients from 15 independent families with adRP in which RHO mutations had been excluded in previous examinations were screened for mutations in the RP1 gene by means of direct DNA sequencing. Evaluation of the RP1 phenotype in patients included funduscopy, kinetic perimetry, dark adapted final threshold test, standard electroretinography and, in one case, multifocal electroretinography. RESULTS: One novel nonsense mutation (Lys778ter) in one of these 15 patients was detected. Cosegregation of the mutation with the disease phenotype could be established in the index patient's family. The phenotype comprises variable expression of clinical disease probably including one case of incomplete penetrance, a onset of symptoms beginning in adulthood, and evidence of regionally varying retinal function loss. CONCLUSION: The Lys778ter mutation localises inside the critical region harbouring all mutations described so far. The ophthalmic findings support previous observations that variation of disease expression appears as a typical feature of the RP1 phenotype.

Aged↗

PubMed2001

CNGA3 mutations in hereditary cone photoreceptor disorders.

We recently showed that mutations in the CNGA3 gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated channel cause autosomal recessive complete achromatopsia linked to chromosome 2q11. We now report the results of a first comprehensive screening for CNGA3 mutations in a cohort of 258 additional independent families with hereditary cone photoreceptor disorders. CNGA3 mutations were detected not only in patients with the complete form of achromatopsia but also in incomplete achromats with residual cone photoreceptor function and (rarely) in patients with evidence for severe progressive cone dystrophy. In total, mutations were identified in 53 independent families comprising 38 new CNGA3 mutations, in addition to the 8 mutations reported elsewhere. Apparently, both mutant alleles were identified in 47 families, including 16 families with presumed homozygous mutations and 31 families with two heterozygous mutations. Single heterozygous mutations were identified in six additional families. The majority of all known CNGA3 mutations (39/46) are amino acid substitutions compared with only four stop-codon mutations, two 1-bp insertions and one 3-bp in-frame deletion. The missense mutations mostly affect amino acids conserved among the members of the cyclic nucleotide gated (CNG) channel family and cluster at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Several mutations were identified recurrently (e.g., R277C, R283W, R436W, and F547L). These four mutations account for 41.8% of all detected mutant CNGA3 alleles. Haplotype analysis suggests that the R436W and F547L mutant alleles have multiple origins, whereas we found evidence that the R283W alleles, which are particularly frequent among patients from Scandinavia and northern Italy, have a common origin.

Amino Acid Sequence↗

PubMed2001

Quantitation of heteroplasmy in mitochondrial DNA mutations by primer extension using Vent(R)(exo-) DNA polymerase and RFLP analysis.

In this report we describe a simple and rapid protocol for reliable quantitation of mitochondrial DNA (mtDNA) mutations, which is basically a modification of the traditional polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) analysis technique. Up to now, the PCR/RFLP method has been of limited use for the accurate determination of ratios of mutant and wild type molecules, largely owing to the formation of heteroduplex molecules by PCR and incompleteness of restriction digestion. In order to overcome this problem, we have introduced a single-step primer extension reaction using Vent(R)(exo-) DNA polymerase and a fluorescence-labeled primer to the standard assay. The labeled homoduplex molecules are then digested with a restriction endonuclease, and the nucleic acids fractionated on an automated DNA sequencer equipped with GENESCAN analysis software. The amount of mutant mtDNA is readily estimated from fluorescence intensities of the wild-type and mutant mtDNA fragments corrected for incomplete digestion as monitored by a homologous control fragment. The accuracy of the improved protocol was determined by constructing standard curves obtained from defined mixtures of genomic DNA containing homoplasmic wild-type and mutant mtDNA. The expected values were obtained, with an observed correlation coefficient of 0.997 and a typical variability of +/-5% between repeated measurements. Further validation of the protocol is provided by the screening of five patients and unaffected subjects carrying the guanine to adenine transition at the nucleotide 3460 of the mitochondrial genome responsible for the mitochondrial disorder of Leber's hereditary optic neuropathy.

DNA Mutational Analysis↗

PubMed2001

OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.

We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.

Adolescent↗

PubMed2001

Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene.

Mutations in the crumbs homologue 1 (CRB1) gene cause a specific form of retinitis pigmentosa (RP) that is designated "RP12" and is characterized by a preserved para-arteriolar retinal pigment epithelium (PPRPE) and by severe loss of vision at age <20 years. Because of the early onset of disease in patients who have RP with PPRPE, we considered CRB1 to be a good candidate gene for Leber congenital amaurosis (LCA). Mutations were detected in 7 (13%) of 52 patients with LCA from the Netherlands, Germany, and the United States. In addition, CRB1 mutations were detected in five of nine patients who had RP with Coats-like exudative vasculopathy, a relatively rare complication of RP that may progress to partial or total retinal detachment. Given that four of five patients had developed the complication in one eye and that not all siblings with RP have the complication, CRB1 mutations should be considered an important risk factor for the Coats-like reaction, although its development may require additional genetic or environmental factors. Although no clear-cut genotype-phenotype correlation could be established, patients with LCA, which is the most severe retinal dystrophy, carry null alleles more frequently than do patients with RP. Our findings suggest that CRB1 mutations are a frequent cause of LCA and are strongly associated with the development of Coats-like exudative vasculopathy in patients with RP.

Adult↗

PubMed2001

Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain.

NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.

Alleles↗

PubMed2001

Macular dystrophy with protan genotype and phenotype studied with cone type specific ERGs.

PURPOSE: To determine the L- and M-cone driven ERG responses in a male patient with macular dystrophy and a protan phenotype. METHODS: We measured large field ERG thresholds to stimuli which modulated exclusively the L- or the M-cones or the two in various combinations (both in-phase and in counterphase). In none of the stimuli, the S-cones were modulated. Additionally, standard and multifocal ERGs were measured. Analysis of the L- and M-cone pigment genes was performed by means of PCR, RFLP analysis and DNA sequencing techniques. RESULTS: Macular dystrophy was revealed by the markedly abnormal multifocal ERGs in presence of near normal standard ERGs. The large field ERG responses were exclusively driven by the M-cones with enlarged thresholds when compared with otherwise normal protanopes. In addition, the M-cone driven ERG response phases were abnormal. Pigment gene analysis confirmed a protan genotype with the presence of a single 5'red/3'green hybrid pigment gene. CONCLUSIONS: Our novel stimulus technique allows a reliable analysis of the separate cone pathways even in cases with macular dysfunction. The increased thresholds and the abnormal phase behavior of the M-cone driven ERGs reflect altered mechanisms of the retinal physiology in this patient. The data strongly suggest that the macular dystrophy and the protanopia have independent origins.

Adult↗

PubMed2001

Complete form of X-linked congenital stationary night blindness: refined mapping and evidence of genetic homogeneity.

A number of distinct, partly non-overlapping genetic loci have been reported for the complete type of X-linked congenital stationary night blindness (CSNB1), suggesting genetic heterogeneity. In order to refine the localization of the CSNB1 gene and to demonstrate genetic homogeneity, linkage analysis was performed in two large CSNB1 families. Clinical features consistent with the diagnosis of CSNB1 were documented in five patients from a German seven-generation kindred by full ophthalmological examination including psychophysical and electroretinographical testing. Haplotype analysis in 30 members of the large German family was performed with 38 polymorphic markers predominantly covering the critical region. Linkage analyses defined a locus for CSNB1 with flanking markers DXS8042 and DXS228, refining the interval to 2.5 cM in Xp11.4. In addition, two-point linkage analysis was carried out using the MLINK computer program. In agreement with meiotic breakpoints, lod scores of 3.0 and greater were obtained for markers located to the proximal site of the former 5 cM CSNB consensus interval. A large Dutch CSNB1 family was re-evaluated with markers from the Xp11.4 region, and supports the CSNB1 minimal interval found in the German family. Together with previous results from three unrelated families from Sweden, Sardinia and Great Britain, our results provide evidence of genetic homogeneity in the disorder. Subsequent mutation analyses in CSNB1 patients revealed no pathogenic sequence alterations in DFFRX and CASK genes, but retain candidates for other diseases mapping to that region.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2001

Case populations must match the respective disease model: Genotype diversity causes linkage disequilibrium mapping failure in monogenic disorders.

Traditional linkage analysis in large families is the most promising approach for mapping disease genes of monogenic heritable disorders when the number of informative meioses is sufficient. With rare diseases, however, the low availability of informative pedigrees poses a significant limitation. As an adjunct to family linkage methods, association studies based on the investigation of individual haplotypes from a number of unrelated patients (i.e. linkage disequilibrium analysis) have recently been employed in mapping hereditary disease loci. However, such haplotype analysis is hampered by a number of effects that influence statistical evaluation, e.g. i) population history and size, ii) allele and haplotype frequencies in the respective population(s), iii) heterogeneous mutation and natural selection processes, and iv) small sample sizes of patient groups. The purpose of the present study was to determine the utility and limitations of haplotype-based genetic mapping in estimating the location of the NYX gene, which has recently been identified as the causative gene for a rare inherited retinal disorder known as the complete type of X-linked congenital stationary night blindness (CSNB1). For this purpose we recapitulated haplotypes and tested for linkage disequilibrium in 20 unrelated male CSNB1 patients from three European populations and 44 healthy individuals. All subjects were genotyped for 17 polymorphic microsatellite loci covering the Xp11.4 region with an average marker density of approximately 0.29 cM. We found that a precise model to describe mutations at loci that erroneously break up linkage is highly required, and that the case population must match the respective disease model.

Adolescent↗

PubMed2001

Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy.

PURPOSE: To investigate the segregation pattern of the mitochondrial DNA mutation at nucleotide position 3460 responsible for Leber's hereditary optic neuropathy (LHON) and to determine the prevalence of heteroplasmy for the three primary LHON mutations at positions 11778, 3460, and 14484. METHODS: Segregation analysis was performed in a cross-sectional study by determining the level of heteroplasmy in blood leukocytes of 23 LHON patients and unaffected carriers from four unrelated families. One family comprising two affected and three unaffected carriers was followed over 5.5 years for a longitudinal segregation analysis of heteroplasmy. The percentage of mutant mtDNA was determined using a novel procedure of fluorescence-based primer extension and restriction fragment length polymorphism analysis. The prevalence of heteroplasmy was assessed by determining the number of genealogically unrelated LHON pedigrees with heteroplasmic maternal family members from the LHON patient records of the Department of Ophthalmology, University of Tübingen, Germany. RESULTS: The authors observed a marked variability in the degree of heteroplasmy levels within each pedigree and a tendency toward a higher mutant allele frequency in offspring generations. Disease expression was correlated with higher levels of mutant mtDNA molecules. Longitudinal analysis revealed no statistically significant decrease in the heteroplasmy level in the family studied but a reduction of 11% and 12% in one affected and one unaffected individual, respectively. In 167 genealogically unrelated LHON families the prevalence of heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484 LHON mutations, respectively. CONCLUSIONS: Cross-sectional studies of heteroplasmy for the 3460 LHON mutation suggest that the genotype shifts toward a higher mutational load in offspring generations. Long-term decrease in the blood mutant load in single cases indicates negative selection of the mutant allele in the hematopoietic cell system. The prevalence of heteroplasmy varies significantly between the different primary LHON mutations, suggesting genotypical differences in disease expression.

Chromosome Segregation↗

PubMed2001

Slow and fast rod ERG pathways in patients with X-linked complete stationary night blindness carrying mutations in the NYX gene.

PURPOSE: To study the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients carrying mutations in the NYX gene, which has been recently identified as the cause of the complete form of congenital stationary night blindness, CSNB1. METHODS: Twenty eyes of 11 patients with CSNB1 who had nondetectable standard ERG rod b-waves were involved in the study. Scotopic ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic trolands. sec (scot td. sec) were measured at a flicker frequency of 15 Hz. ERG signals to flicker intensities between -3.37 and -1.97 and between -1.17 and -0.57 log scot td. sec were considered to represent primarily the slow and fast rod ERG pathway, respectively. Additionally, standard ERGs were performed. Twenty-two normal volunteers served as control subjects. RESULTS: For the slow rod ERG pathway, all patients exhibited ERG signals that were indistinguishable from noise. Accordingly, there was no systematic phase behavior for the slow rod signals. For the fast rod ERG pathway, the signals were significantly above noise, but they were significantly reduced in amplitude and advanced in phase. CONCLUSIONS: There is evidence that the slow and the fast rod ERG signals can be attributed to the rod bipolar-AII cell pathway and the rod-cone-coupling pathway, respectively. The current study provides evidence to suggest that a defective NYX gene product (nyctalopin) prevents detectable signal transmission through ON rod bipolar cells, but there is a residual transmission through rod-cone gap junctions in CSNB1, possibly through the OFF cone pathway.

Adolescent↗

PubMed2000

Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21.

Achromatopsia is an autosomal recessive disorder featuring total colour blindness, photophobia, reduced visual acuity and nystagmus. While mutations in the CNGA3 gene on chromosome 2q11 are responsible for achromatopsia in a subset of patients, previous linkage studies have localized another achromatopsia locus, ACHM3, on chromosome 8q21. Using achromatopsia families in which CNGA3 mutations have been excluded, we refined the ACHM3 locus to a 3.7 cM region enclosed by markers D8S1838 and D8S273. Two yeast artificial chromosome (YAC) contigs covering nearly the entire ACHM3 interval were constructed. Database searches with YAC content sequences identified two overlapping high throughput genomic sequencing phase (HTGS) entries which contained sequences homologous to the murine cng6 gene encoding the putative beta-subunit of the cone photoreceptor cGMP-gated channel. Using RT-PCR and RACE, we identified and cloned the human cDNA homologue, designated CNGB3, which encodes an 809 amino acid polypeptide. Northern blot analysis revealed a major transcript of approximately 4.4 kb specifically expressed in the retina. The human CNGB3 gene consists of 18 exons distributed over approximately 200 kb of genomic sequence. Analysis of the CNGB3 gene in achromats revealed six different mutations including a missense mutation (S435F), two stop codon mutations (R203X and E336X), a 1 bp and an 8 bp deletion (1148delC and 819-826del) and a putative splice site mutation of intron 13. The 1148delC mutation was identified recurrently in several families, and in total was present on 11 of 22 disease chromosomes segregating in our families.

Amino Acid Sequence↗

PubMed2000

[A case of Leber optic neuropathy with a new point mutation in the cytochrome b gene].

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is associated with mutations in the mitochondrial DNA (mtDNA). We report the clinical and molecular genetic findings of a patient who does not carry any of the common LHON mutations. METHODS: Clinical data were collected for the affected patient and two unaffected maternal family members. Complete sequence analysis of the mtDNA protein coding region was performed in the affected patient. RESULTS: Clinical examination of the affected patient showed typical features of LHON. A nucleotide exchange was detected at np14894 replacing an evolutionarily conserved phenylalanine by a leucine in the cytochrome b gene. The mutation was also present in two unaffected maternal family members, but absent in 60 other LHON lineages and 175 unrelated controls. CONCLUSIONS: Cytochrome b plays an important role in the electron transport chain of mitochondrial oxidative phosphorylation, and some mutations in the gene encoding cytochrome b have been associated with LHON. Our results may imply that the novel mutation at np14894 is responsible for LHON in this family.

Adult↗

PubMed2000

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

Amino Acid Sequence↗

PubMed2000

The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.

X-linked congenital stationary night blindness (XLCSNB) is characterized by impaired scotopic vision with associated ocular symptoms such as myopia, hyperopia, nystagmus and reduced visual acuity. Genetic mapping in families with XLCSNB revealed two different loci on the proximal short arm of the X chromosome. These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form. The CSNB1 locus has been mapped to a 5-cM linkage interval in Xp11.4 (refs 2,5-7). Here we construct and analyse a contig between the markers DXS993 and DXS228, leading to the identification of a new gene mutated in CSNB1 patients. It is partially deleted in 3 families and mutation analysis in a further 21 families detected another 13 different mutations. This gene, designated NYX, encodes a protein of 481 amino acids (nyctalopin) and is expressed at low levels in tissues including retina, brain, testis and muscle. The predicted polypeptide is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein with 11 typical and 2 cysteine-rich, leucine-rich repeats (LRRs). This motif is important for protein-protein interactions and members of the LRR superfamily are involved in cell adhesion and axon guidance. Future functional analysis of nyctalopin might therefore give insight into the fine-regulation of cell-cell contacts in the retina.

Amino Acid Motifs↗