[Show abstract][Hide abstract] ABSTRACT: Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration.
[Show abstract][Hide abstract] ABSTRACT: The gene for autosomal recessive retinitis pigmentosa (RP12) with preserved para-arteriolar retinal pigment epithelium was previously mapped close to the F13B gene in region 1q31-->q32.1. A 4-Mb yeast artificial chromosome contig spanning this interval was constructed to facilitate cloning of the RP12 gene. The contig comprises 25 sequence-tagged sites, polymorphic markers, and single-copy probes, including five newly obtained probes. The contig orders the F13B and HF1 genes, as well as five expressed sequence tags, with respect to the integrated genetic map of this region. Homozygosity mapping resulted in refinement of the candidate gene locus for RP12 to a 1. 3-cM region. Currently, approximately 1 Mb of the contig is represented in P1-derived artificial chromosome (PAC) clones. Direct screening of a cDNA library derived from neural retina with PACs resulted in identification of the human elongation factor 1alpha pseudogene (EEF1AL11) and a human ribosomal protein L30 pseudogene (RPL30). A physical and genetic map covering the entire RP12 candidate gene region was constructed.
Cytogenetics and cell genetics 01/1999; 84(1-2):22-7.
[Show abstract][Hide abstract] ABSTRACT: Retinitis pigmentosa (RP) denotes a group of hereditary retinal dystrophies, characterized by the early onset of night blindness followed by a progressive loss of the visual field. The primary defect underlying RP affects the function of the rod photoreceptor cell, and, subsequently, mostly unknown molecular and cellular mechanisms trigger the apoptotic degeneration of these photoreceptor cells. Retinitis pigmentosa is very heterogeneous, both phenotypically and genetically. In this review we propose a tentative classification of RP based on the functional systems affected by the mutated proteins. This classification connects the variety of phenotypes to the mutations and segregation patterns observed in RP. Current progress in the identification of the molecular defects underlying RP reveals that at least three distinct functional mechanisms may be affected: 1) the daily renewal and shedding of the photoreceptor outer segments, 2) the visual transduction cascade, and 3) the retinol (vitamin A) metabolism. The first group includes the rhodopsin and peripherin/RDS genes, and mutations in these genes often result in a dominant phenotype. The second group is predominantly associated with a recessive phenotype that results, as we argue, from continuous inactivation of the transduction pathway. Disturbances in the retinal metabolism seem to be associated with equal rod and cone involvement and the presence of deposits in the retinal pigment epithelium.
Survey of Ophthalmology 01/1999; 43(4):321-34. · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.
[Show abstract][Hide abstract] ABSTRACT: Choroideremia (CHM) is an X-linked recessive eye disease that results from mutations involving the Rab escort protein-1 (REP-1) gene. In 18 patients deletions of different sizes have been found. Two females suffering from CHM were reported to have translocations that disrupt the REP-1 gene. In 22 patients, small mutations have been identified. Interestingly, these are all nonsense, frameshift or splice-site mutations; with one possible exception, missense mutations have not been found. This comprises all the known mutations in the disease.
Human Mutation 02/1997; 9(2):110-7. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Audiograms were traced or additionally performed on 23 Usher's syndrome patients in 10 Dutch multi-affected families, all linked to chromosome 1q (USH2A locus). Serial audiograms, available in 13 patients, were used for a regression analysis of binaural pure tone average on age (follow-up, 9 to 32 years) to test for "significant progression," ie, a significant regression coefficient, here called the "annual threshold increase" (ATI, expressed in decibels per year). A significant ATI (> 1 dB/y) was observed in 3 patients. Analysis of variance of ATI demonstrated significant heterogeneity; hearing loss was either stable or progressive. This implies a significant clinical heterogeneity. A similar analysis performed on our progressive USH2A cases and "type III" cases previously reported by others (ATI of 1 to 5 dB/y), some of which were recently linked to chromosome 3q (USH3 locus), failed to show any significant heterogeneity in the progression of hearing loss.
The Annals of otology, rhinology, and laryngology 12/1996; 105(12):962-7. · 1.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder of the optic nerves. It has been proposed that the specific mutations in the mitochondrial DNA (mtDNA) that are associated with LHON require and X-chromosomally encoded permissive factor in order to become expressed. This would explain both the preponderance of male patients and the fact that most carriers of specific mtDNA mutations remain unaffected. Although linkage studies have been negative so far, the existence of such a factor has not been ruled out. We investigated the genealogical data of 24 large LHON pedigrees and concluded that the presumed X-linked factor would be recessively inherited and that at least 57% of the affected females would be heterozygous. Therefore, these females must be the victim of nonrandom X-chromosomal inactivation (skewed lyonization). However, analysis of X-chromosomal methylation patterns in 16 LHON-affected females revealed substantial skewing in only 15%-20% of cases, which is not significantly different from the patterns in 49 controls. Moreover, we found the frequency of LHON in daughters of affected heterozygous females to be twice to three times as high as in daughters of unaffected heterozygous females, which cannot be explained by an X-chromosomally inherited factor. We concluded that the results of our investigations do not support the hypothesis that LHON is a digenic disease with an X-linked factor being the main cause of loss of vision in the presence of relevant mtDNA mutations.
Human Genetics 05/1996; 97(4):500-5. · 4.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a previous study on a large pedigree from a genetically isolated population in the Netherlands, we localized a gene for autosomal recessive retinitis pigmentosa with paraarteriolar preservation of the retinal pigment epithelium (PPRPE) on the long arm of chromosome 1. In this study, we present an integrated genetic map of the target region. The resulting genetic order of the markers was used to construct haplotypes and to screen for key-recombinants in the pedigree. The obligate RP12 region was reduced from 16 cM to 5 cM between the markers D1S533 and CACNL1A3. The CACNL1A3 and phosducin (PDC) genes were placed outside the candidate gene region, thereby excluding the involvement of these genes in retinitis pigmentosa with PPRPE. Our data result in the following order of the markers and genes in the region 1q31 --> q32.1: cen-D1S158-(D1S238-D1S422)/PDC- D1S533-RP12/(F13B-D1S413)-CACNL1A3-DIS4 77-D1S306-D1S53-tel.
Cytogenetics and cell genetics 01/1996; 73(1-2):81-5.
[Show abstract][Hide abstract] ABSTRACT: Thirty-seven patients, comprising 24 familial cases and 13 isolated patients with Usher syndrome type II (USH2), underwent ophthalmologic examination. Based on the degree of hearing loss, normal vestibular function, and gene-linkage analysis, familial cases were assumed to have USH2A. An analysis of genetic heterogeneity failed to reveal the presence of a second locus in the Dutch population. Although the patients appear to belong to a genetically homogeneous group, remarkable ophthalmologic variability was found. Corrected visual acuity decreased with age and remarkable differences in visual acuity were found within one family. Fundoscopic findings were classified as type A if attenuated vessels and bone corpuscles in all quadrants were found or as type B if findings other than these were found. The prevalence of type A significantly increased with age.
[Show abstract][Hide abstract] ABSTRACT: Seventeen obligate carriers from nine families with autosomal recessive Usher syndrome type I underwent otological, audiological, vestibular, and ophthalmological examination in order to identify possible manifestations of heterozygosity. Linkage studies were performed and six families showed linkage to chromosome region 11q13.5 while 3 families have so far failed to show linkage to the candidate regions. Eight obligate carriers had an abnormal pure-tone audiogram. Two different audiometric patterns could be distinguished when hearing loss was corrected for age and sex. Four carriers (24%) had significant sensorineural hearing loss (SNHL) which increased at higher frequencies. The other 13 carriers had SNHL of about 10 dB at 0.25 and 0.5 kHz, but less at higher frequencies. Vestibular findings were generally normal. Electro-oculography demonstrated a significant lower mean light peak/dark trough ratio in Usher type I carriers compared to normal control individuals. The methods used in this study were found not to be specific enough to clinically identify carriers of Usher type I syndrome. Nevertheless it is remarkable that a number of obligate carriers showed significant audiological and ophthalmological abnormalities.
American Journal of Medical Genetics 12/1995; 59(3):375-9.
[Show abstract][Hide abstract] ABSTRACT: The electron transfer activity of Complex I of the respiratory chain and Complex I-linked ATP synthesis were investigated in leukocytes of four males affected by Leber hereditary optic neuropathy and a mutation in the ND6 gene at nucleotide position 14,484 of mtDNA. The electron transfer activity in leukocytes of the patients was about 35% of that in control leukocytes, whereas the Complex I-linked ATP synthesis showed a decrease of only about 20%. This demonstrates that all three mtDNA mutations that are clearly associated with Leber hereditary optic neuropathy result in deficiency of Complex I. However, the relationship between these mtDNA mutations, the function of Complex I and the phenotypic profile remains elusive.
Biochemical and Biophysical Research Communications 11/1995; 215(3):1001-5. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Three mtDNA point mutations at nucleotide position (np) 3460, at np 11778 and at np 14484, are thought to be of primary importance in the pathogenesis of Leber hereditary optic neuropathy (LHON), a maternally inherited disease characterized by subacute central vision loss. These mutations are present in genes coding for subunits of complex I (NADH dehydrogenase) of the respiratory chain, occur exclusively in LHON maternal pedigrees, and have never been reported to occur together. Johns and Neufeld postulated that an mtDNA mutation at np 9438, in the gene coding for one of the subunits (COX III) of complex IV (cytochrome c oxidase), was also of primary importance. Johns and Neufeld (1993) found this mutation, which changed a conserved glycine to a serine, in 5 unrelated LHON probands who did not carry one of the presently known primary mutations, but they did not find it in 400 controls. However, the role of this sequence variant has been questioned in the Journal when it has been found to occur in apparently healthy African and Cuban individuals. Subsequently, Johns et al. described this mutation in two Cuban individuals presenting with optic and peripheral neuropathy. 22 refs., 1 fig., 1 tab.
The American Journal of Human Genetics 11/1995; 57(4):954-7. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leber hereditary optic neuropathy (LHON) is a heritable disorder, clinically characterized by rapidly progressive loss of central vision due to severe bilateral optic atrophy. The disease predominantly occurs in men. The clinical picture shows marked interpersonal variation. Recently it has been established that LHON is associated with at least three specific mutations in the mitochondrial DNA, which explains the non-Mendelian, strictly maternal inheritance. The presence of different mutations implies that there is not only clinical but also genetical heterogeneity. Since all matrilinear family members carry the mtDNA mutation involved, but only 30-50% of males and 5-15% of the females develop LHON, other etiological factors, hereditary or exogenous, remain to be discovered. Identification of these factors is of major importance to understand the pathogenesis and to explore the possibilities for therapy and prevention of LHON.
Nederlands tijdschrift voor geneeskunde 08/1995; 139(26):1327-31.
[Show abstract][Hide abstract] ABSTRACT: Batten disease, or the juvenile form of neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder manifesting with progressive blindness, seizures, and dementia, leading to an early death. The CLN3 locus which is involved in Batten disease had been localized to chromosome 16p11.2. Linkage disequilibrium has been observed between CLN3 and polymorphic microsatellite markers D16S288, D16S299, and D16S298, making carrier detection and prenatal diagnosis by haplotype analysis possible. For the purpose of carrier detection, haplotypes from Dutch Batten patients and their families were constructed. Most patients share the same D16S298 allele, suggesting the presence of a founder effect in the Dutch population. In a large inbred Dutch family, in which Batten disease occurs with high frequency, haplotype analysis has been carried out with high accuracy for carrier detection.
American Journal of Medical Genetics 07/1995; 57(2):333-7.