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1.
Am J Hum Genet ; 108(12): 2368-2384, 2021 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-34800363

RESUMEN

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.


Asunto(s)
Ataxia/genética , Epilepsia/genética , Pérdida Auditiva/genética , Complejo Cetoglutarato Deshidrogenasa/genética , Mutación , Trastornos del Neurodesarrollo/genética , Trastornos de la Visión/genética , Alelos , Animales , Células Cultivadas , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Drosophila melanogaster/genética , Salud de la Familia , Femenino , Fibroblastos , Humanos , Masculino , Empalme del ARN
2.
Brain ; 146(7): 2730-2738, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-36860166

RESUMEN

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.


Asunto(s)
Distonía , Trastornos Distónicos , Humanos , Distonía/genética , Trastornos Distónicos/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Mutación Missense , Linaje , Proteínas/genética
3.
Int J Mol Sci ; 25(14)2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39063023

RESUMEN

Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic-dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.


Asunto(s)
Cardiomiopatías , Dinaminas , Mutación , Humanos , Femenino , Dinaminas/genética , Cardiomiopatías/genética , Mutación/genética , Lactante , Resultado Fatal , Encefalopatías/genética , Encefalopatías/patología , GTP Fosfohidrolasas/genética
4.
Cerebellum ; 22(6): 1313-1319, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36447112

RESUMEN

AFG3-like matrix AAA peptidase subunit 2 gene (AFG3L2, OMIM * 604,581) biallelic mutations lead to autosomal recessive spastic ataxia-5 SPAX5, OMIM # 614,487), a rare hereditary form of ataxia. The clinical spectrum includes early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy (PME). In Italy, the epidemiology of the disease is probably underestimated. The advent of next generation sequencing (NGS) technologies has speeded up the diagnosis of hereditary diseases and increased the percentage of diagnosis of rare disorders, such as the rare hereditary ataxia groups. Here, we describe two patients from two different villages in the province of Ferrara, who manifested a different clinical ataxia-plus history, although carrying the same biallelic mutation in AFG3L2 (p.Met625Ile) identified through NGS analysis.


Asunto(s)
Ataxia Cerebelosa , Degeneraciones Espinocerebelosas , Humanos , ATPasas Asociadas con Actividades Celulares Diversas/genética , Degeneraciones Espinocerebelosas/genética , Ataxia Cerebelosa/genética , Mutación/genética , Italia , Proteasas ATP-Dependientes/genética
5.
Ann Neurol ; 88(1): 18-32, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32219868

RESUMEN

OBJECTIVE: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. METHODS: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. RESULTS: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. INTERPRETATION: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.


Asunto(s)
Proteasas ATP-Dependientes/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , GTP Fosfohidrolasas/genética , Atrofia Óptica/genética , Enfermedades del Nervio Óptico/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Secuenciación del Exoma , Adulto Joven
6.
Hum Mutat ; 41(10): 1745-1750, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32652806

RESUMEN

Biallelic mutations in the C1QBP gene have been associated with mitochondrial cardiomyopathy and combined respiratory-chain deficiencies, with variable onset (including intrauterine or neonatal forms), phenotypes, and severity. We studied two unrelated adult patients from consanguineous families, presenting with progressive external ophthalmoplegia (PEO), mitochondrial myopathy, and without any heart involvement. Muscle biopsies from both patients showed typical mitochondrial alterations and the presence of multiple mitochondrial DNA deletions, whereas biochemical defects of the respiratory chain were present only in one subject. Using next-generation sequencing approaches, we identified homozygous mutations in C1QBP. Immunoblot analyses in patients' muscle samples revealed a strong reduction in the amount of the C1QBP protein and varied impairment of respiratory chain complexes, correlating with disease severity. Despite the original study indicated C1QBP mutations as causative for mitochondrial cardiomyopathy, our data indicate that mutations in C1QBP have to be considered in subjects with PEO phenotype or primary mitochondrial myopathy and without cardiomyopathy.


Asunto(s)
Proteínas Portadoras , Miopatías Mitocondriales , Proteínas Mitocondriales , Oftalmoplejía Externa Progresiva Crónica , Oftalmoplejía , Proteínas Portadoras/genética , ADN Mitocondrial/genética , Homocigoto , Humanos , Miopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Mutación , Oftalmoplejía/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Oftalmoplejía Externa Progresiva Crónica/patología
7.
Hum Mutat ; 40(5): 601-618, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30801875

RESUMEN

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.


Asunto(s)
Dinaminas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/genética , Músculos/metabolismo , Músculos/patología , Biomarcadores , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Análisis Mutacional de ADN , Dinaminas/química , Fibroblastos/metabolismo , Estudios de Asociación Genética/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Modelos Biológicos , Músculos/ultraestructura , Mutación , Conformación Proteica , Relación Estructura-Actividad
8.
Bioinformatics ; 34(17): 3038-3040, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29668842

RESUMEN

Summary: Exome sequencing approach is extensively used in research and diagnostic laboratories to discover pathological variants and study genetic architecture of human diseases. However, a significant proportion of identified genetic variants are actually false positive calls, and this pose serious challenge for variants interpretation. Here, we propose a new tool named Genomic vARiants FIltering by dEep Learning moDels in NGS (GARFIELD-NGS), which rely on deep learning models to dissect false and true variants in exome sequencing experiments performed with Illumina or ION platforms. GARFIELD-NGS showed strong performances for both SNP and INDEL variants (AUC 0.71-0.98) and outperformed established hard filters. The method is robust also at low coverage down to 30X and can be applied on data generated with the recent Illumina two-colour chemistry. GARFIELD-NGS processes standard VCF file and produces a regular VCF output. Thus, it can be easily integrated in existing analysis pipeline, allowing application of different thresholds based on desired level of sensitivity and specificity. Availability and implementation: GARFIELD-NGS available at https://github.com/gedoardo83/GARFIELD-NGS. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Aprendizaje Profundo , Genómica , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación INDEL , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos
9.
Am J Med Genet A ; 179(5): 827-831, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30773800

RESUMEN

Here we report on a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency, associated with mitochondrial impairment. Targeted clinical exome sequencing led to the identification of a homozygous missense variant in OTX2. Since only dominant mutations within OTX2 have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an OTX2 recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to OTX2. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in LETM1, and heterozygous rare variants in AFG3L2 and POLG. All three genes encode mitochondrial proteins and the last two are known to be associated with ataxia, a neurological sign present also in the father of the proband. With our study, we aim to encourage the integration of NGS data with a detailed analysis of clinical description and family history in order to unravel composite genotypes sometimes associated with complicated phenotypes.


Asunto(s)
Ataxia/genética , Homocigoto , Hipopituitarismo/genética , Mitocondrias/genética , Enfermedades Musculares/genética , Mutación , Factores de Transcripción Otx/genética , Distrofias Retinianas/genética , Adulto , Anciano , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Ataxia/diagnóstico , ADN Mitocondrial , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Hipopituitarismo/diagnóstico , Cariotipificación , Masculino , Mitocondrias/metabolismo , Enfermedades Musculares/diagnóstico , Factores de Transcripción Otx/química , Linaje , Fenotipo , Distrofias Retinianas/diagnóstico
10.
J Hum Genet ; 63(5): 563-568, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29531337

RESUMEN

Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.


Asunto(s)
Secuenciación del Exoma , Heterocigoto , Intrones , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Mutación Missense , ARN Mensajero/genética , Alelos , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Expresión Génica , Haplotipos , Humanos , Lactante , Linfocitos/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Proteínas Mitocondriales , Linaje , Fenotipo
11.
J Med Genet ; 54(12): 815-824, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29079705

RESUMEN

BACKGROUND: Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron-sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband. METHODS: A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient's specimens and yeast models were investigated. RESULTS: Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation. CONCLUSION: We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported.


Asunto(s)
Genes Dominantes , Proteínas Hierro-Azufre/genética , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Mutación , Secuencia de Aminoácidos , Biomarcadores , Biopsia , Biología Computacional/métodos , Electroencefalografía , Electromiografía , Fibroblastos/metabolismo , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas Hierro-Azufre/química , Imagen por Resonancia Magnética , Masculino , Modelos Moleculares , Músculo Esquelético/patología , Linaje , Fenotipo , Análisis de Secuencia de ADN , Relación Estructura-Actividad , Adulto Joven
12.
Metab Brain Dis ; 33(3): 805-812, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29359243

RESUMEN

A homoallelic missense founder mutation of the iron-sulfur cluster assembly 2 (ISCA2) gene has been recently reported in six cases affected by an autosomal recessive infantile neurodegenerative mitochondrial disorder. We documented a case of a 2-month-old girl presenting with severe hypotonia and nystagmus, who rapidly deteriorated and died at the age of three months. Increased cerebral spinal fluid level of lactate, documented also at the brain spectroscopy, involvement of the cortex, restricted diffusion of white and gray matter abnormalities, sparing of the corpus callosum and extensive involvement of the spinal cord were observed. Her clinical presenting features and course as well as some neuroradiological findings mimicked those of early-onset leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL). The analysis of the mitochondrial respiratory chain function showed a reduced activity of complexes II and IV. The girl harboured two heterozygous mutations in the ISCA2 gene. A comprehensive review of the literature and a comparison with the cases of early onset LBSL enabled us to highlight significant differences in the clinical, biochemical and neuroradiological phenotype between the two conditions, which also emerged from the comparison with the other 6 reported cases of ISCA2 gene mutation previously reported. In summary, this represents the second report ever published associating ISCA2 gene mutation with a mitochondrial leukoencephalopathy, with a different genetic mechanism to the previous cases. Molecular analysis of ISCA2 should be included in the genetic panel for the diagnosis of early onset mitochondrial leukoencephalopathies.


Asunto(s)
Encéfalo/metabolismo , Proteínas Hierro-Azufre/genética , Ácido Láctico/metabolismo , Leucoencefalopatías/genética , Médula Espinal/metabolismo , Femenino , Humanos , Lactante , Leucoencefalopatías/diagnóstico , Mitocondrias/metabolismo , Mutación
13.
Biochim Biophys Acta ; 1857(8): 1326-1335, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26968897

RESUMEN

Next Generation Sequencing (NGS) technologies are revolutionizing the diagnostic screening for rare disease entities, including primary mitochondrial disorders, particularly those caused by nuclear gene defects. NGS approaches are able to identify the causative gene defects in small families and even single individuals, unsuitable for investigation by traditional linkage analysis. These technologies are contributing to fill the gap between mitochondrial disease cases defined on the basis of clinical, neuroimaging and biochemical readouts, which still outnumber by approximately 50% the cases for which a molecular-genetic diagnosis is attained. We have been using a combined, two-step strategy, based on targeted genes panel as a first NGS screening, followed by whole exome sequencing (WES) in still unsolved cases, to analyze a large cohort of subjects, that failed to show mutations in mtDNA and in ad hoc sets of specific nuclear genes, sequenced by the Sanger's method. Not only this approach has allowed us to reach molecular diagnosis in a significant fraction (20%) of these difficult cases, but it has also revealed unexpected and conceptually new findings. These include the possibility of marked variable penetrance of recessive mutations, the identification of large-scale DNA rearrangements, which explain spuriously heterozygous cases, and the association of mutations in known genes with unusual, previously unreported clinical phenotypes. Importantly, WES on selected cases has unraveled the presence of pathogenic mutations in genes encoding non-mitochondrial proteins (e.g. the transcription factor E4F1), an observation that further expands the intricate genetics of mitochondrial disease and suggests a new area of investigation in mitochondrial medicine. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.


Asunto(s)
ADN Mitocondrial/genética , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Mutación , Proteínas Represoras/genética , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Estudios de Cohortes , ADN Mitocondrial/metabolismo , Transporte de Electrón , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Exoma , Femenino , Expresión Génica , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Lactante , Masculino , Mitocondrias/patología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Datos de Secuencia Molecular , Proteínas Represoras/metabolismo , Alineación de Secuencia , Ubiquitina-Proteína Ligasas , Adulto Joven
15.
Brain ; 139(Pt 3): 782-94, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26912632

RESUMEN

This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years.


Asunto(s)
Leucoencefalopatía Multifocal Progresiva/diagnóstico , Leucoencefalopatía Multifocal Progresiva/genética , Imagen por Resonancia Magnética , Proteínas Mitocondriales/genética , Chaperonas Moleculares/genética , Mutación/genética , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Datos de Secuencia Molecular , Saccharomyces cerevisiae
16.
Hum Mutat ; 37(9): 898-903, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27328748

RESUMEN

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.


Asunto(s)
Encefalopatías/genética , GTP Fosfohidrolasas/genética , Proteínas Asociadas a Microtúbulos/genética , Mitocondrias/patología , Proteínas Mitocondriales/genética , Mutación , Adolescente , Alelos , Encefalopatías/patología , Preescolar , Codón sin Sentido , Dinaminas , Mutación del Sistema de Lectura , Humanos , Masculino , Dinámicas Mitocondriales , Linaje , Peroxisomas/patología
17.
Am J Med Genet A ; 170(11): 3004-3007, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27549011

RESUMEN

The FARS2 gene encodes the mitochondrial phenylalanyl-tRNA synthetase and is implicated in autosomal recessive combined oxidative phosphorylation deficiency 14, a clinical condition characterized by infantile onset epilepsy and encephalopathy. Mutations in FARS2 have been reported in only few patients, but a detailed description of seizures, electroencephalographic patterns, magnetic resonance imaging findings, and long-term follow-up is still needed. We provide a clinical report of a child with FARS2-related disease manifesting drug-resistant infantile spasms associated with focal seizures. By comparative genomic hybridization analysis we identified a heterozygous microdeletion in the short arm of chromosome 6, inherited from the mother, that encompasses the first coding exon of FARS2. By sequencing of the FARS2 gene we identified a variant c.1156C>G; p.(R386G), inherited from the father. By using standard spectrophotometric techniques in skin fibroblasts, we found a combined abnormality of complexes I and IV of the mitochondrial respiratory chain. The main clinical features of the patient included axial hypotonia, mild distal hypertonia, and psychomotor delay. The magnetic resonance imaging showed microcephaly, frontal cerebral atrophy, and signal changes of dentate nuclei. At the age of 3 years and 6 months, the patient was still under treatment with vigabatrin and he has been seizure free for the last 23 months. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Proteínas Mitocondriales/genética , Mutación , Fenilalanina-ARNt Ligasa/genética , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Anticonvulsivantes/uso terapéutico , Encéfalo/patología , Deleción Cromosómica , Cromosomas Humanos Par 6 , Hibridación Genómica Comparativa , Electroencefalografía , Exones , Heterocigoto , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Fenotipo , Espasmos Infantiles/tratamiento farmacológico , Resultado del Tratamiento
19.
Hum Mutat ; 36(5): 489-95, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25726928

RESUMEN

Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.


Asunto(s)
Encefalopatías/genética , Encefalopatías/patología , Calcinosis/genética , Mutación , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Alelos , Sustitución de Aminoácidos , Encefalopatías/diagnóstico , Análisis Mutacional de ADN , Exones , Estudios de Asociación Genética , Variación Genética , Humanos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismo
20.
Psychiatry Clin Neurosci ; 69(2): 77-83, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25211641

RESUMEN

AIMS: Primary familial brain calcification (PFBC) is a rare disorder characterized by abnormal deposits of calcium in the basal ganglia and cerebellum. PFBC can present with a spectrum of neuropsychiatric symptoms resembling those seen in dementia and schizophrenia. Mutations in a few genes have been identified as causing PFBC: namely, the SLC20A2 gene that codes for the sodium-dependent phosphate transporter and the PDGFRB gene that codes for the platelet-derived growth factor receptor ß (PDGF-Rß). A recent study identified mutations in PDGFB coding for PDGF-B, the main ligand for PDGF-Rß, in six families with PFBC. Here we report the first Japanese family with PFBC carrying a mutation in PDGFB, which causes the substitution of an arginine with a stop codon at amino acid 149 of the PDGF-B protein (p. Arg149*). METHODS: Clinical histories and computed tomography scan images were provided. Sanger sequencing was performed for the exome analysis of SLC20A2 and PDGFB genes. RESULTS: One family member began to complain of auditory hallucination at 16 years of age and had been treated for schizophrenia. His father suffered from memory and gait disturbances in his late 60s. A computed tomography scan revealed a symmetrical area of calcification over the basal ganglia in both cases. A known mutation in PDGFB (c.445C>T, p.Arg149*) was consistently detected in both PFBC cases by Sanger sequencing. No mutations in SLC20A2 were detected. CONCLUSIONS: Our findings suggest that this mutation in PDGF-B is responsible for PFBC in this Japanese family and that abnormal PDGF signaling may be involved in the pathophysiology of certain psychiatric disorders.


Asunto(s)
Encefalopatías/genética , Calcinosis/genética , Proteínas Proto-Oncogénicas c-sis/genética , Adulto , Anciano , Encefalopatías/patología , Encefalopatías/fisiopatología , Calcinosis/patología , Calcinosis/fisiopatología , Exoma , Padre , Humanos , Japón , Masculino , Núcleo Familiar
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