Search

Background: Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin., Methods: We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast Yarrowia lipolytica ., Results: We identified compound heterozygote NDUFS2 disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast Y. lipolytica ortholog NUCM , the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively., Conclusions: Biallelism for NDUFS2 mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic NDUFS2 mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of NDUFS2 mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophy responsible for blindness or severe visual impairment at birth or within the first months of life. Up to date, ten LCA genes have been identified. Three of them account for ca. 43% of families and are responsible for a congenital severe stationary cone-rod dystrophy (Type I, 60% of LCA) while the seven remaining genes account for 32% of patients and are responsible for a progressive yet severe rod-cone dystrophy (Type II, 40% of LCA ). Recently, mutations in LCA5, encoding the ciliary protein lebercilin, were reported to be a rare cause of leber congenital amaurosis. The purpose of this study was to evaluate the involvement of this novel gene and to look for genotype-phenotype correlations. Here we report the identification of three novel LCA5 mutations (3/3 homozygous) in three families confirming the modest implication of this gene in our series (3/179; 1.7%). Besides, we suggest that the phenotype of these patients affected with a particularly severe form of LCA type II may represent a continuum with LCA type I., ((c) 2007 Wiley-Liss, Inc.)

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration responsible for congenital blindness. Hitherto, 13 LCA genes have been mapped, nine of which have been identified. Recently, mutations in the NPHP6/CEP290 gene were shown to account for Joubert and Senior-Loken syndromes and to represent a frequent cause of isolated LCA. All LCA patients shared an intronic mutation resulting in an aberrantly spliced transcript and low levels of wild-type transcript that was believed to explain the absence of cerebellar and renal involvement in these patients. Here, we confirm the high frequency of NPHP6/CEP290 mutations in our series of LCA families hailing worldwide (22%). However, we show that conversely to other LCA genes, NPHP6 is involved in families of European descent only (38/38). A total of 24 different mutations were found, 23 of which are novel (one founder mutation in the North region of France). All mutations but two were either nonsense, frameshift, or splice-site changes. The common NPHP6/CEP290 intronic mutation accounted for 43% (33/76) of all disease alleles. Twelve families did not carry this common intronic mutation. At least 10 out of them harboured two mutations expected to truncate the protein questioning the relevance of the assumption according to which the retinal-restricted phenotype in LCA patient could be due to a residual NPHP6/CEP290 activity. Finally, we show that all patients were affected with the cone-rod subtype of the disease whatever their NPHP6/CEP290 genotype., (Copyright 2007 Wiley-Liss, Inc.)

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium, but they are involved in strikingly different physiologic pathways, resulting in an unforeseeable pathophysiologic variety. This broad genetic and physiologic heterogeneity, which could greatly increase in the coming years, hinders molecular diagnosis in LCA patients. Genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here we report a comprehensive mutational analysis of all the known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% of patients. GUCY2D accounted for by far the largest part of the LCA cases in our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%) and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited in the search for phenotype variations. Genotype-phenotype correlations were found that made it possible to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rod-cone dystrophy. In addition, objective ophthalmologic data subdivided each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the onerous task of genotyping new patients, but only if the most precise clinical history since birth is available.

Leber congenital amaurosis (LCA), the most early-onset and severe form of all inherited retinal dystrophies, is responsible for congenital blindness. Ten LCA genes have been mapped, and seven of these have been identified. Because some of these genes are involved in the visual cycle, we regarded the retinal pigment epithelium and photoreceptor-specific retinal dehydrogenase (RDH) genes as candidate genes in LCA. Studying a series of 110 unrelated patients with LCA, we found mutations in the photoreceptor-specific RDH12 gene in a significant subset of patients (4.1%). Interestingly, all patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia.

Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. Eight LCA loci have been mapped, but only six out of eight genes have been hitherto identified. A genome-wide screen for homozygosity was conducted in a large consanguineous family originating from Palestine, for which no mutation was found in any of the six known LCA genes and that excluded the LCA3 and LCA5 loci. Evidence for homozygosity, however, was found in all affected patients of the family on chromosome 1q31, a region in which the human homologue of the Drosophila melanogaster crumbs gene (CRB1) has been mapped. Consequently, we proposed a hypothesis that the disease-causing mutation in this family might lie in an unexplored region of this LCA gene. As a matter of fact, while no mutation was found in any of the 11 CRB1 exons originally reported, we identified a 10-bp (del 4121-4130) deletion segregating with the disease in a later reported 12th exon lying in the 3' end of the gene. Interestingly, this deletion disrupts an amino acid sequence that was shown to be crucial for the function of the protein in the Drosophila counterpart (CRB).

Background: Leber's congenital amaurosis (LCA) encompasses the most precocious and severe forms of inherited retinal dystrophy, displaying very significant visual handicap at or soon after birth. Among the currently identified mutations, alterations in the gene coding for retinal pigment epithelium 65-kDa protein (RPE65) lead to LCA2. Existing animal models for LCA2 (RPE65(-/-) null mice and naturally occurring RPE65(-/-) Briard dogs) exhibit near normal retinal histology at birth, although no recordable photofunction can be detected. Structural degeneration in both cases occurs with delayed onset, cone death generally preceding that of rods., Methods: We obtained retinal tissue from a voluntarily aborted embryo of an LCA2 carrier in order to compare histopathology and immunohistochemistry with age-matched normal foetal retina., Results: Compared to normal retinas, affected retina displayed cell loss and thinning of the outer nuclear (photoreceptor) layer, decreased immunoreactivity for key phototransduction proteins, and aberrant synaptic and inner retinal organisation. The gene mutation abolished detectable expression of RPE65 within the retinal pigment epithelium (RPE) of affected eyes, and ultrastructural examination revealed the presence of lipid and vesicular inclusions not seen in normal RPE. In addition, mutant eyes demonstrated thickening, detachment and collagen fibril disorganisation in the underlying Bruch's membrane, and the choroid was distended and abnormally vascularised, in comparison with controls., Conclusions: Such data contrast with the late-onset ocular changes observed in animal models, indicating caution should be exercised when inferring human retinal pathophysiology from information based on other species., (Copyright 2002 John Wiley & Sons, Ltd.)