RESUMEN
Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.
Asunto(s)
Tronco Encefálico/anomalías , Mutación de Línea Germinal , Neuroblastoma/genética , Neuroblastoma/patología , Proteínas Tirosina Quinasas Receptoras/genética , Adulto , Quinasa de Linfoma Anaplásico , Sistema Nervioso Central/embriología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Mutación Missense , Neuroblastoma/congénito , Oncogenes , SíndromeRESUMEN
Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.
Asunto(s)
Ataxia Cerebelosa/genética , Convulsiones/genética , Ubiquinona/deficiencia , Adolescente , Adulto , Secuencia de Aminoácidos , Benzoquinonas/análisis , Encéfalo/enzimología , Encéfalo/patología , Femenino , Haplotipos , Humanos , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Músculo Esquelético/química , Mutación Missense , Linaje , Ubiquinona/análisis , Ubiquinona/genéticaRESUMEN
Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS) as it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q10 deficiency is a rare, but possibly treatable, autosomal recessive condition with four major clinical presentations, an encephalomyopathic form, a generalized infantile variant with severe encephalopathy and renal disease, a myopathic form and an ataxic form. The diagnosis of ubiquinone deficiency is supported by respiratory chain analysis and eventually by the quantification of CoQ10 in patient tissues. We review here the infantile and pediatric quinone deficiency diseases as well as the clinical improvement after oral CoQ10 therapy. The clinical heterogeneity of ubiquinone deficiency is suggestive of a genetic heterogeneity that should be related to the large number of enzymes, and corresponding genes, involved in ubiquinone biosynthesis.
Asunto(s)
Enfermedades del Sistema Nervioso/metabolismo , Ubiquinona/análogos & derivados , Niño , Preescolar , Coenzimas/deficiencia , Coenzimas/metabolismo , Humanos , Lactante , Recién Nacido , Mitocondrias/metabolismo , Modelos Biológicos , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Oxígeno/metabolismo , Consumo de Oxígeno , Succinatos/metabolismo , Ubiquinona/deficiencia , Ubiquinona/genética , Ubiquinona/metabolismoRESUMEN
Coenzyme Q10 (CoQ10) plays a pivotal role in oxidative phosphorylation (OXPHOS), as it distributes electrons among the various dehydrogenases and the cytochrome segments of the respiratory chain. We have identified 2 novel inborn errors of CoQ10 biosynthesis in 2 distinct families. In both cases, enzymologic studies showed that quinone-dependent OXPHOS activities were in the range of the lowest control values, while OXPHOS enzyme activities were normal. CoQ10 deficiency was confirmed by restoration of normal OXPHOS activities after addition of quinone. A genome-wide search for homozygosity in family 1 identified a region of chromosome 10 encompassing the gene prenyldiphosphate synthase, subunit 1 (PDSS1), which encodes the human ortholog of the yeast COQ1 gene, a key enzyme of CoQ10 synthesis. Sequencing of PDSS1 identified a homozygous nucleotide substitution modifying a conserved amino acid of the protein (D308E). In the second family, direct sequencing of OH-benzoate polyprenyltransferase (COQ2), the human ortholog of the yeast COQ2 gene, identified a single base pair frameshift deletion resulting in a premature stop codon (c.1198delT, N401fsX415). Transformation of yeast Deltacoq1 and Deltacoq2 strains by mutant yeast COQ1 and mutant human COQ2 genes, respectively, resulted in defective growth on respiratory medium, indicating that these mutations are indeed the cause of OXPHOS deficiency.
Asunto(s)
Transferasas Alquil y Aril/genética , Enfermedades Mitocondriales/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Adolescente , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Preescolar , Cromosomas Humanos Par 10/genética , Coenzimas , Femenino , Prueba de Complementación Genética , Homocigoto , Humanos , Masculino , Enfermedades Mitocondriales/enzimología , Datos de Secuencia Molecular , Mutación , Fosforilación Oxidativa , Linaje , Análisis de Secuencia de ADN , Ubiquinona/biosíntesis , Ubiquinona/genética , Levaduras/genéticaRESUMEN
The mitochondrial respiratory chain (RC) results from the expression of both mitochondrial and nuclear genes. The number of disease-causing mutations in nuclear genes is steadily growing and mitochondrial DNA (mtDNA) deletions and mutations account for no more than 15-20% of pediatric patients. Unfortunately, the disease-causing mutations have been identified for only a small number of patients. Thus, elucidating the genetic bases of RC is both essential for genetic diagnosis of patients and for fundamental knowledge of these disorders. The molecular diagnostics of mitochondrial disorders come under both genetic diagnosis and research. Indeed, identification of a new gene in a specific patient allows to perform genetic diagnosis in other families and identification of mutations in already known disease-causing genes allows to constitute a cohort of patients for further functional studies. Thus, elucidating the genetic bases of RC deficiency is an essential task that needs the use of several appropriate strategies. Fine phenotypage of patients and candidate gene screening is the first step for the constitution of a well-characterized cohort of patients. Genetic mapping has to be used in large families. This approach is greatly enhanced in the case of consanguineous families. The consanguinity of the parents should also lead to test genetic markers surrounding the gene loci rather than to directly sequence several candidate genes. However, the main problem is encountered in the cases of sporadic cases for which no genetic approaches can be developed. In these cases, functional complementation by human chromosomes or cDNA is the only presently available strategy.