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1.
Mitochondrion ; 47: 294-297, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30743023

RESUMEN

Adult-onset Leigh syndrome is a rare but important manifestation of mitochondrial disease. We report a 17 year old female who presented with subacute encephalopathy, brainstem and extrapyramidal signs, raised CSF lactate, and symmetrical hyperintensities in the basal ganglia on T2-weighted cerebral MRI. The presence of cytochrome c oxidase deficient fibres in muscle tissue prompted sequencing of the entire mitochondrial genome which revealed the novel stop codon mutation m.6579G>A; p.Gly226X in MT-CO1. Here we present the case and review the clinicopathological and molecular spectrum of previously reported MT-CO1 truncating mutations.


Asunto(s)
Codón de Terminación , Complejo IV de Transporte de Electrones/genética , Enfermedad de Leigh/genética , Atrofias Ópticas Hereditarias/genética , Adulto , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Humanos , Enfermedad de Leigh/enzimología , Atrofias Ópticas Hereditarias/enzimología
2.
Hum Mutat ; 21(2): 170-1, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12552567

RESUMEN

Cone rod dystrophy 5 (CORD5) is an autosomal dominant retinal disease that primarily affects cone function. The locus has previously been mapped to human chromosome 17p12-p13 between the markers D17S926/D17S849 and D17S945/D17S804. One of our "unaffected" recombinant individual from family 1175 was subsequently found to cross through this interval. Reexamination revealed that he was in fact mildly affected. This expanded the minimum candidate region. Direct sequencing of the GUCY2D and other candidate genes within this interval was carried out on 2 American families affected with CORD5. There was an R838C missense mutation within the GUCY2D gene in one and a R838H missense mutation in another families. The previously reported mutations for CORD6 are clustered at the same position within the gene. These results indicate that both CORD5 (MIM# 600977) and CORD6 (MIM# 601777) are actually the same disease. We conclude that significant variability in expression and incomplete penetrance exists even within one family.


Asunto(s)
Guanilato Ciclasa/genética , Mutación/genética , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/genética , Penetrancia , Adolescente , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Animales , Arginina/genética , Bovinos , Niño , Preescolar , Perros , Echinacea/genética , Femenino , Genes Dominantes/genética , Marcadores Genéticos/genética , Histidina/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Proteínas de Plantas/genética , Ratas , Recombinación Genética/genética
3.
Hum Mutat ; 20(4): 322-3, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12325031

RESUMEN

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies. It is a genetically heterogeneous condition as six disease-causing genes have been hitherto identified. Among them, RETGC1 (GUCY2D), is more frequently implicated in our series of LCA patients. Interestingly, 70 % of the families with RETGC1 mutations are originating from Mediterranean countries, the remaining families (30%) being originating from various countries across the world. Here, we report, the identification of the same homozygous RETGC1 nonsense mutation in three unrelated and non-consanguineous LCA families of Finnish origin, suggesting a founder effect. Interestingly, no linkage desequilibrium was found using polymorphic markers flanking the RETGC1 gene, supporting the view that the mutation is very ancient. Haplotype studies and Bayesian calculation point the founder mutation to 150 generations (95% credible interval 80-240 generations), i.e., 3000 years ago.


Asunto(s)
Ceguera/genética , Efecto Fundador , Guanina , Mutación/genética , Atrofias Ópticas Hereditarias/genética , Linaje , Eliminación de Secuencia/genética , Ceguera/congénito , Ceguera/enzimología , GMP Cíclico/metabolismo , Femenino , Finlandia , Guanilato Ciclasa/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Núcleo Familiar , Atrofias Ópticas Hereditarias/enzimología , Polimorfismo de Nucleótido Simple/genética
4.
Invest Ophthalmol Vis Sci ; 42(6): 1190-2, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11328726

RESUMEN

PURPOSE: Leber congenital amaurosis (LCA) is the earliest and the most severe form of all inherited retinal dystrophies. In 1996, the current investigators ascribed the disease in families linked to the LCA1 locus on chromosome 17p13.1 to mutations in the photoreceptor-specific guanylyl cyclase (retGC-1) gene. So far, 22 different mutations, of which 11 are missense mutations, have been identified in 25 unrelated families. This is a report of the functional analyses of nine of the missense mutations. METHODS: cDNA constructs were generated that contained the retGC-1 missense mutations identified in patients related to the LCA1 locus. Mutants were expressed in COS7 cells and assayed for their ability to hydrolyze guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). RESULTS: All mutations lying in the catalytic domain showed a complete abolition of cyclase activity. In contrast, only one mutation lying in the extracellular domain also resulted in a severely reduced catalytic activity, whereas the others showed completely normal activity. CONCLUSIONS: More than half the mutations identified in patients related to the LCA1 locus are truncating mutations expected to result in a total abolition of retGC-1 activity. Concerning missense mutations, half of them lying in the catalytic domain of the protein also result in the complete inability of the mutant cyclases to hydrolyze GTP into cGMP in vitro. In contrast, missense mutations lying in the extracellular domain, except one affecting the initiation codon, showed normal catalytic activity of retGC-1. Nevertheless, considering that all patients related to the LCA1 locus displayed the same phenotype, it can be assumed that all missense mutations would have the same dramatic consequences on protein activity in vivo as truncation mutations.


Asunto(s)
Ceguera/enzimología , Guanilato Ciclasa/genética , Mutación Missense , Atrofias Ópticas Hereditarias/enzimología , Receptores de Superficie Celular , Segmento Externo de la Célula en Bastón/enzimología , Animales , Células COS , Cromosomas Humanos Par 17/genética , GMP Cíclico/metabolismo , Análisis Mutacional de ADN , Ligamiento Genético , Guanosina Trifosfato/metabolismo , Guanilato Ciclasa/metabolismo , Humanos , Hidrólisis
5.
J Inherit Metab Dis ; 23(7): 730-44, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11117434

RESUMEN

We employed a microphotometric approach to examine whether a defect in the mitochondrial respiratory complex I expected in Leber hereditary optic neuropathy (LHON) as the consequence of a mtDNA (11778G>A) mutation in the ND4 gene coding for a subunit of the respiratory complex I can be detected at the single-cell level. Genetically stable fibroblast cell lines were established from skin biopsies of two members of a Chinese Indonesian family with LHON. The fibroblasts were homoplasmic for the 11778G>A mutation. The activity of the respiratory complex I was examined histochemically by staining for NADH-tetrazolium reductase. The histochemical staining showed a typical pattern with an apparent concentration of the activity around the nucleus, suggested as the reflection of the gradient in the thickness of the unsectioned fibroblast cells. Microphotometric quantification of the staining intensity showed that the activity is linear for at least 60 min. The activity shows a discontinuity in its Arrhenius kinetics with a break point at 13.0-13.5 degrees C (activation energy at 50-58 J/mol and 209-238 J/mol above and below the break temperature, respectively), indicating the membrane association of the NADH-tetrazolium reductase activity. Both patients showed lower fibroblast NADH-tetrazolium reductase activity, with a reduction of degrees 30%. Our results demonstrate the utility of microphotometric analysis in the study of biochemical defects associated with mutations in the mtDNA.


Asunto(s)
Fibroblastos/enzimología , NADH Tetrazolio Reductasa/deficiencia , Atrofias Ópticas Hereditarias/enzimología , Línea Celular , Fibroblastos/citología , Humanos , NADH Tetrazolio Reductasa/metabolismo , Atrofias Ópticas Hereditarias/genética , Atrofias Ópticas Hereditarias/patología , Mutación Puntual
6.
Korean J Ophthalmol ; 14(1): 45-8, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10933019

RESUMEN

Leber's hereditary optic neuropathy (LHON) is caused by a point mutation in the mitochondrial deoxynucleic acid (mtDNA) and accounts for 30% of bilateral optic atrophy of unknown etiology. The authors found a Korean family with mtDNA mutations in the nucleotide positions (np) 11778 and np 4216. This is the first report confirming a secondary mtDNA np 4216 mutation in Koreans, as well as the first report of a Korean family harboring both primary and the secondary mutations that the authors are aware of.


Asunto(s)
Alelos , Grupo Citocromo b/genética , ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/genética , Atrofias Ópticas Hereditarias/genética , Mutación Puntual , Adolescente , Adulto , Grupo Citocromo b/metabolismo , Análisis Mutacional de ADN , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Masculino , Atrofias Ópticas Hereditarias/enzimología , Linaje , Reacción en Cadena de la Polimerasa , Agudeza Visual
7.
Eur J Hum Genet ; 8(8): 578-82, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10951519

RESUMEN

Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Genetic heterogeneity of LCA has been suspected since the report by Waardenburg of normal children born to affected parents. In 1995 we localised the first disease causing gene, LCA1, to chromosome 17p13 and confirmed the genetic heterogeneity. In 1996 we ascribed LCA1 to mutations in the photoreceptor-specific guanylate cyclase gene (retGC1). Here, we report on the screening of the whole coding sequence of the retGC1 gene in 118 patients affected with LCA. We found 22 different mutations in 24 unrelated families originating from various countries of the world. It is worth noting that all retGC1 mutations consistently caused congenital cone-rod dystrophy in our series, confirming the previous genotype-phenotype correlations we were able to establish. RetGC1 is an essential protein implicated in the phototransduction cascade, especially in the recovery of the dark state after the excitation process of photoreceptor cells by light stimulation. We postulate that the retGC1 mutations hinder the restoration of the basal level of cGMP of cone and rod photoreceptor cells, leading to a situation equivalent to consistent light exposure during photoreceptor development, explaining the severity of the visual disorder at birth.


Asunto(s)
Ceguera/congénito , Guanilato Ciclasa/genética , Mutación , Atrofias Ópticas Hereditarias/genética , Receptores de Superficie Celular , Segmento Externo de la Célula en Bastón/enzimología , Ceguera/enzimología , Ceguera/genética , Cromosomas Humanos Par 17 , GMP Cíclico/metabolismo , Femenino , Heterogeneidad Genética , Genotipo , Humanos , Masculino , Atrofias Ópticas Hereditarias/enzimología , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN
9.
Hum Genet ; 104(1): 99-105, 1999 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10071200

RESUMEN

The family of diacylglycerol kinases (DAGKs) is known to play an important role in signal transduction linked to phospholipid turnover. In the fruitfly Drosophila melanogaster, a human DAGK ortholog, DGK2, was shown to underlie the phenotype of the visual mutant retinal degeneration A (rdgA). Previously, the gene encoding a novel member of the human DAGK family, termed DAGK3, was cloned and demonstrated to be abundantly expressed in the human retina. Based on these findings we reasoned that DAGK3 might be an excellent candidate gene for a human eye disease. In the present study, we report the genomic organization of the human DAGK3 gene, which spans over 30 kb of genomic DNA interrupted by 23 introns. In addition, we have mapped the gene locus by fluorescence in situ hybridization to 3q27-28, overlapping the chromosomal region known to contain the gene underlying dominant optic atrophy (OPA1), the most common form of hereditary atrophy of the optic nerve. Mutational analysis of the entire coding region of DAGK3 in 19 unrelated German OPA1 patients has not revealed any disease-causing mutations, therefore excluding DAGK3 as a major cause underlying OPA1.


Asunto(s)
Mapeo Cromosómico , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/fisiología , Genes Dominantes/genética , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Cromosomas Humanos Par 3/genética , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje
10.
Biochemistry ; 38(2): 509-15, 1999 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-9888789

RESUMEN

ROS-GC1 is the original member of the subfamily of membrane guanylate cyclases with two Ca2+ switches, which have been defined as CRM1 and CRM2. These are separately located within the intracellular domain of the cyclase. CRM1 switches on the enzyme at nanomolar concentrations of Ca2+ and is linked with phototransduction; the other stimulates at micromolar Ca2+ concentrations and is predicted to be linked with retinal synaptic activity. Ca2+ acts indirectly via Ca2+-binding proteins, GCAP1 and CD-GCAP. GCAP1 is a modulator of the CRM1 switch, and CD-GCAP turns on the CRM2 switch. A Leber's congenital amaurosis, termed LCA1, involves F514S point mutation in ROS-GC1. The present study shows that the mutation severely damages its intrinsic cyclase activity and inactivates its CRM1 switch but does not affect the CRM2 switch. In addition, on the basis of the established modulatory features of ROS-GC1, it is predicted that, in two other forms of LCA1 involving deletion of nt 460C or 693C, there is a frameshift in ROS-GC1 gene, which results in the nonexpression of the cyclase. For the first time, the findings define the linkage of distinct molecular forms of LCA to ROS-GC1 in precise biochemical terms; they also explain the reasons for the insufficient production of cyclic GMP in photoreceptors to sustain phototransduction, which ultimately leads to the degeneration of the photoreceptors.


Asunto(s)
Ligamiento Genético , Guanilato Ciclasa/genética , Mutación , Atrofias Ópticas Hereditarias/genética , Receptores de Superficie Celular , Segmento Externo de la Célula en Bastón/enzimología , Animales , Calcio/fisiología , Proteínas de Unión al Calcio/fisiología , Proteínas Activadoras de la Guanilato-Ciclasa , Humanos , Atrofias Ópticas Hereditarias/enzimología , Fenilalanina/genética , Serina/genética
12.
FEBS Lett ; 433(1-2): 93-7, 1998 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-9738940

RESUMEN

Mutations in the human mtDNA gene encoding subunit III of cytochrome c oxidase (CO) have been reported to cause MELAS and LHON. Poracoccus denitrificans cells expressing substitutions homologous to these MELAS- and LHON-causing mutations had lower growth yield than wild type cells and lower efficiency of proton pumping by CO (e.g. lower H+/e ratio and lower deltapsi), but had similar CO activity. These results indicate that both substitutions (F263L > A212T) cause intrinsic uncoupling, which may be the direct cause of the diseases. These results also suggest that subunit III is involved in proton pumping.


Asunto(s)
ADN Mitocondrial/genética , Complejo IV de Transporte de Electrones/genética , Síndrome MELAS/genética , Atrofias Ópticas Hereditarias/genética , Ácido Ascórbico/farmacología , Eliminación de Gen , Expresión Génica , Humanos , Cinética , Síndrome MELAS/enzimología , Compuestos Onio/metabolismo , Atrofias Ópticas Hereditarias/enzimología , Compuestos Organofosforados/metabolismo , Paracoccus denitrificans/enzimología , Paracoccus denitrificans/genética , Paracoccus denitrificans/crecimiento & desarrollo , Bombas de Protones/metabolismo , Tetrametilfenilendiamina/farmacología
13.
Biochemistry ; 37(34): 11792-6, 1998 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-9718301

RESUMEN

The human mitochondrial ND1/3460 mutation changes Ala52 to Thr in the ND1 subunit of Complex I, and causes Leber's hereditary optic neuropathy (LHON) [Huoponen et al. (1991) Am. J. Hum. Genet. 48, 1147]. We have used a bacterial counterpart of Complex I, NDH-1 from Paracoccus denitrificans, for studying the effect of mutations in the ND1 subunit on the enzymatic activity. The LHON mutation as well as several other mutations in strictly conserved amino acids in its vicinity were introduced into the NQO8 subunit of NDH-1, a bacterial homologue of ND1. The enzymatic activity of the mutants in the presence of hexammineruthenium (rotenone-insensitive) and ubiquinone-1 (rotenone-sensitive) were assayed. In addition, the kinetics of the interaction of selected mutant enzymes with ubiquinone-1, ubiquinone-2, and decylubiquinone was studied. The results suggest that the mutated residues play an important role in ubiquinone reduction by Complex I.


Asunto(s)
Secuencia Conservada/genética , ADN Mitocondrial/genética , Mutagénesis Sitio-Dirigida , NAD(P)H Deshidrogenasa (Quinona)/genética , Paracoccus denitrificans/genética , Alanina/genética , Secuencia de Aminoácidos , Animales , Ácido Aspártico/genética , ADN Mitocondrial/metabolismo , Complejo I de Transporte de Electrón , Glutamina/genética , Humanos , Lisina/genética , Datos de Secuencia Molecular , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/genética , Paracoccus denitrificans/enzimología , Quinona Reductasas/genética , Quinona Reductasas/metabolismo
14.
Hum Mol Genet ; 7(7): 1179-84, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9618177

RESUMEN

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal-specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.


Asunto(s)
Guanilato Ciclasa/genética , Mutación/genética , Atrofias Ópticas Hereditarias/genética , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Bastones/patología , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/patología , Linaje , Fenotipo , Células Fotorreceptoras Retinianas Conos/enzimología , Células Fotorreceptoras Retinianas Bastones/enzimología
15.
Proc Natl Acad Sci U S A ; 95(3): 1271-6, 1998 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-9448321

RESUMEN

The retinas of the retinal degeneration (rd) chicken are fully developed and possess normal morphology at hatching but fail to respond to light stimulation. Analyses of retinal cGMP, the internal messenger of phototransduction, show that the amount of cGMP in predegenerate, fully developed rd/rd photoreceptors is 5-10 times less than that seen in normal photoreceptor cells. We show that the low levels of cGMP in rd chicken retina are a consequence of a null mutation in the photoreceptor guanylate cyclase (GC1) gene. Thus, the rd chicken is a model for human Leber's congenital amaurosis. Absence of GC1 in rd retina prevents phototransduction and affects survival of rods and cones but does not interfere with normal photoreceptor development.


Asunto(s)
Proteínas de Unión al Calcio/genética , Mutación del Sistema de Lectura , Guanilato Ciclasa/genética , Receptores de Superficie Celular/genética , Degeneración Retiniana/enzimología , Degeneración Retiniana/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Ceguera/enzimología , Ceguera/genética , Proteínas de Unión al Calcio/fisiología , Pollos , Clonación Molecular , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Reordenamiento Génico , Guanilato Ciclasa/química , Proteínas Activadoras de la Guanilato-Ciclasa , Humanos , Datos de Secuencia Molecular , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/genética , Fenotipo , Células Fotorreceptoras/metabolismo , Receptores de Superficie Celular/química , Visión Ocular/genética
16.
Neurology ; 48(6): 1623-32, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9191778

RESUMEN

To clarify the bioenergetic relevance of mtDNA mutations in Leber's hereditary optic neuropathy (LHON), we investigated affected individuals and healthy carriers from six Italian LHON families harboring the 11778/ND4 and the 3460/ND1 mtDNA mutations. The enzymatic activities of mitochondrial complex I and its sensitivity to the potent inhibitors rotenone and rolliniastatin-2 were studied in mitochondrial particles from platelets, in correlation with mtDNA analysis of platelets and leukocytes. In platelets homoplasmic for mutant mtDNA, both 11778/ND4 and 3460/ND1 mutations induced resistance to rotenone and the 3460/ND1 mutation also provoked a marked decrease in the specific activity of complex I. Individuals heteroplasmic in platelets for either mutation showed normal biochemical features, indicating functional complementation of wild-type mtDNA. There was no correlation between the clinical status and mtDNA homo/heteroplasmy in platelets, but the biochemical features correlated with the mitochondrial genotype of platelets. In some cases, the degree of mtDNA heteroplasmy differed in platelets and leukocytes from the same individual with a prevalence of wild-type mtDNA in the platelets. These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues. The differential tissue heteroplasmy may be more relevant than previously thought in determining disease penetrance.


Asunto(s)
ADN Mitocondrial/análisis , Atrofias Ópticas Hereditarias/genética , Mutación Puntual , Antineoplásicos Fitogénicos/farmacología , Plaquetas/química , Plaquetas/ultraestructura , Salud de la Familia , Femenino , Furanos/farmacología , Genotipo , Humanos , Leucocitos/química , Leucocitos/ultraestructura , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/genética , NADH NADPH Oxidorreductasas/metabolismo , Atrofias Ópticas Hereditarias/enzimología , Linaje , Fenotipo , Rotenona/farmacología
17.
Biochem Biophys Res Commun ; 234(2): 511-5, 1997 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-9177303

RESUMEN

DNA sequence analysis of the gene encoding subunit 6 of the NADH-ubiquinone-oxidoreductase complex (ND6) in human mitochondria was performed in 25 independent patients who suffer from Lebers hereditary optic neuropathy (LHON). In 10 cases the well-known LHON mutation at nucleotide position (np) 14484 was detected. Furthermore, silent substitutions at np14167 and np14527 and missense mutations at np14498, np14564, np14568, and np14582 were found in individual patients. The np14498 and np14568 mutations were found in patients who present a typical clinical picture and course of LHON but lack any of the canonical mtDNA mutations. The np14568 mutation, which replaces a moderately conserved glycine by a serine residue, was observed in a single male patient and subsequently excluded in 175 independent controls. The mutation at np14498, which replaces an evolutionarily highly conserved tyrosine with a cysteine, was found in a multigeneration family with four affected members, the eldest carrying a heteroplasmic mixture of mutated and wildtype mtDNA molecules. None of 170 analyzed control subjects carried this mutation. These findings provide evidence that several allelic ND6 gene mutations may be involved in Lebers hereditary optic neuropathy.


Asunto(s)
ADN Mitocondrial/genética , NADH NADPH Oxidorreductasas/genética , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/genética , Mutación Puntual , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Secuencia Conservada , Análisis Mutacional de ADN , Cartilla de ADN/genética , Complejo I de Transporte de Electrón , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Homología de Secuencia de Aminoácido
18.
Nat Genet ; 14(4): 461-4, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8944027

RESUMEN

Leber's congenital amaurosis (LCA, MIM 204,000), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digito-ocular sign of Franceschetti). Hypermetropia and keratoconus frequently develop in the course of the disease. The observation by Waardenburg of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.


Asunto(s)
Ceguera/congénito , Guanilato Ciclasa/genética , Mutación , Atrofias Ópticas Hereditarias/enzimología , Retina/enzimología , Ceguera/enzimología , Ceguera/genética , Cromosomas Humanos Par 17 , GMP Cíclico/metabolismo , Mutación del Sistema de Lectura , Homocigoto , Humanos , Datos de Secuencia Molecular , Atrofias Ópticas Hereditarias/genética , Células Fotorreceptoras/metabolismo , Mapeo Restrictivo
19.
Am J Hum Genet ; 58(4): 703-11, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8644732

RESUMEN

A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-->A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy.


Asunto(s)
ADN Mitocondrial/genética , Distonía/genética , NAD(P)H Deshidrogenasa (Quinona)/deficiencia , NAD(P)H Deshidrogenasa (Quinona)/genética , NADH Deshidrogenasa/genética , Atrofias Ópticas Hereditarias/genética , Adulto , Secuencia de Aminoácidos , Citrato (si)-Sintasa/metabolismo , Análisis Mutacional de ADN , Distonía/complicaciones , Distonía/enzimología , Transporte de Electrón , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculo Esquelético/enzimología , Atrofias Ópticas Hereditarias/complicaciones , Atrofias Ópticas Hereditarias/enzimología , Oxidorreductasas/metabolismo , Linaje , Fenotipo , Mutación Puntual/genética
20.
Mol Cell Biol ; 16(3): 771-7, 1996 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8622678

RESUMEN

A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I.


Asunto(s)
ADN Mitocondrial/genética , NADH Deshidrogenasa/genética , Atrofias Ópticas Hereditarias/genética , Línea Celular Transformada , Herpesvirus Humano 4 , Humanos , Células Híbridas , Mutación , Atrofias Ópticas Hereditarias/enzimología
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