Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 90
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 160(1-2): 177-90, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25594180

RESUMEN

Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia prior to or at the onset of neurodegeneration. The accumulated lipids are peroxidated in the presence of ROS. Reducing LD accumulation in glia and lipid peroxidation via targeted lipase overexpression and/or lowering ROS significantly delays the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice with neuronal mitochondrial defects, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon, and represents an early, transient indicator and promoter of neurodegenerative disease.


Asunto(s)
Gotas Lipídicas/metabolismo , Mitocondrias/metabolismo , Neuroglía/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Noqueados , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuroglía/patología , Neuronas/patología , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo
2.
Am J Hum Genet ; 108(1): 134-147, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33340455

RESUMEN

The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences ("N-end rule"). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.


Asunto(s)
Epilepsia/genética , Hipotiroidismo/genética , Trastornos del Neurodesarrollo/genética , Receptores Notch/genética , Transducción de Señal/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Ano Imperforado/genética , Caenorhabditis elegans/genética , Línea Celular , Displasia Ectodérmica/genética , Trastornos del Crecimiento/genética , Células HEK293 , Pérdida Auditiva Sensorineural/genética , Histonas/genética , Humanos , Discapacidad Intelectual/genética , Ratones , Mutación/genética , Nariz/anomalías , Enfermedades Pancreáticas/genética , Complejo de la Endopetidasa Proteasomal/genética
3.
Cytotherapy ; 26(1): 88-95, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37747395

RESUMEN

BACKGROUND AND AIMS: As cell and gene therapy (CGT) has grown in availability and scope, more unapproved regenerative medicine is being marketed to the public. It is essential that health care providers have sufficient knowledge and comfort to determine whether treatments are properly regulated and address these topics with patients. Due to the applicability of CGT to genetic disease, genetic counselors could be key in providing education and answering patients' questions about these topics. However, previous studies have focused only on physicians' knowledge and comfort with CGT and unapproved regenerative medicine. The purpose of this study was to assess genetic counselors' self-reported knowledge and comfort discussing these topics with patients and to explore what factors predict increased knowledge and comfort. METHODS: The authors designed an online survey distributed to genetic counselors who were part of the National Society of Genetic Counselors Student Research Program e-mail list. The survey addressed genetic counselors' demographics, practice experience with CGT, education about CGT, knowledge and comfort. RESULTS: The survey was completed by 144 genetic counselors. The best predictor of increased knowledge and comfort was experience discussing CGT in practice. In addition, those who worked at an institution at which CGT trials were offered had greater knowledge and comfort. However, most genetic counselors reported their knowledge was not sufficient to address questions from patients, and most had little-to-no knowledge or comfort determining whether a trial was properly regulated. There was no correlation between education and either knowledge or comfort; however, most participants desired more education about these topics. CONCLUSIONS: This study suggests that genetic counselors who (i) have experience with CGT in practice or (ii) work at institutions at which CGT trials are offered may have better knowledge regarding CGT. These results may help identify individuals and/or institutions in whom increasing knowledge regarding CGT could be beneficial. This is crucial as CGT becomes mainstream, leading to more widely marketed unapproved regenerative medicine. Several gaps in knowledge and comfort were identified, including participants' ability to determine whether a treatment is properly regulated. Further research is needed to better characterize the educational needs of genetic counselors surrounding these topics to address these gaps.


Asunto(s)
Consejeros , Asesoramiento Genético , Humanos , Asesoramiento Genético/métodos , Encuestas y Cuestionarios , Tratamiento Basado en Trasplante de Células y Tejidos , Medicina Regenerativa
4.
Genet Med ; 25(11): 100950, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37551667

RESUMEN

PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.


Asunto(s)
Anomalías Múltiples , Discapacidad Intelectual , Micrognatismo , Trastornos del Neurodesarrollo , Humanos , Anomalías Múltiples/genética , Cara , Micrognatismo/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Facies , Fenotipo , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética
5.
Mol Genet Metab ; 140(3): 107668, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37549443

RESUMEN

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.


Asunto(s)
Errores Innatos del Metabolismo Lipídico , Enfermedades Mitocondriales , Enfermedades Musculares , Humanos , Recién Nacido , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Pruebas Genéticas , Variación Genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/genética , Enfermedades Musculares/genética
6.
Int J Mol Sci ; 24(13)2023 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-37445899

RESUMEN

Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. SCS-deficient encephalomyopathy typically presents in infancy and early childhood, with many patients succumbing to the disease during childhood. Common symptoms include abnormal brain MRI, basal ganglia lesions and cerebral atrophy, severe hypotonia, dystonia, progressive psychomotor regression, and growth deficits. Although subunits of SCS were first identified as causal genes for progressive metabolic encephalomyopathy in the early 2000s, recent investigations are now beginning to unravel the pathomechanisms underlying this metabolic disorder. This article reviews the current understanding of SCS function within and outside the TCA cycle as it relates to the complex and multifactorial mechanisms underlying SCS-related mitochondrial encephalomyopathy.


Asunto(s)
Encefalomiopatías Mitocondriales , Succinato-CoA Ligasas , Preescolar , Humanos , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/metabolismo , Mitocondrias/metabolismo , Succinato-CoA Ligasas/genética , Succinato-CoA Ligasas/metabolismo , Estrés Oxidativo
7.
Am J Hum Genet ; 105(3): 493-508, 2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31447100

RESUMEN

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.


Asunto(s)
Senescencia Celular/fisiología , Histonas/fisiología , Aneuploidia , Nucléolo Celular/metabolismo , Niño , Cromatina/metabolismo , Metilación de ADN , Femenino , Histonas/química , Humanos , Lactante , Masculino , Persona de Mediana Edad
8.
Cytogenet Genome Res ; 162(1-2): 40-45, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35139523

RESUMEN

The 16p11.2 duplication is a well-known cause of developmental delay and autism, but there are only 2 previously reported cases of 16p11.2 triplication. Both of the previously reported cases exhibited tandem triplication on a 16p11.2 duplication inherited from 1 parent. We report fraternal twins presenting with developmental delay and 16p11.2 triplication resulting from inheritance of a 16p11.2 duplicated homolog from each parent. This report also reviews the overlapping features in previously published cases of 16p11.2 triplication, and possible implications are discussed.


Asunto(s)
Trastorno Autístico , Trastorno Autístico/genética , Duplicación Cromosómica/genética , Cromosomas Humanos Par 16/genética , Bases de Datos Genéticas , Femenino , Humanos , Masculino , Padres , Fenotipo
9.
Ann Neurol ; 89(4): 828-833, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33443317

RESUMEN

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.


Asunto(s)
Cerebelo/anomalías , Discapacidades del Desarrollo/genética , Distonía/genética , Complejo Mediador/genética , Malformaciones del Sistema Nervioso/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Catarata/genética , Niño , Preescolar , Epilepsia/genética , Variación Genética , Humanos , Lactante , Fenotipo , Secuenciación del Exoma
10.
Am J Hum Genet ; 103(6): 1030-1037, 2018 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-30503518

RESUMEN

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.


Asunto(s)
Anomalías Congénitas/genética , Variación Genética/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Secuencia de Aminoácidos , Encefalopatías/genética , Niño , Discapacidades del Desarrollo/genética , Femenino , Fibroblastos/patología , Fucosiltransferasas/genética , Glicosilación , Guanosina Difosfato Fucosa/genética , Guanosina Difosfato Manosa/genética , Humanos , Masculino , Hipotonía Muscular/genética , Convulsiones/genética , Alineación de Secuencia , Piel/patología , Ubiquitina/genética
12.
J Nutr ; 150(8): 2156-2163, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32492151

RESUMEN

BACKGROUND: Poor lifestyles have been linked to insulin insensitivity/hyperinsulinemia, which may contribute to downstream changes such as inflammation and oxidative damage and the development of chronic diseases. As a biomarker of intracellular oxidative stress, leukocyte mitochondrial DNA copy number (mtDNA-CN) has been related to lifestyle factors including diet and weight. No epidemiologic study has examined the relation between combined insulinemic potential of lifestyle and mtDNA-CN. OBJECTIVES: Our aim was to examine the association between Empirical Lifestyle Index for Hyperinsulinemia (ELIH) and leukocyte mtDNA-CN in US men and women. METHODS: This cross-sectional analysis included 2835 white adults without cancers, diabetes, or cardiovascular disease at blood collection, including 2160 women from the Nurses' Health Study and 675 men from the Health Professionals Follow-Up Study. ELIH is an index based on plasma C-peptide that characterizes the insulinemic potential of lifestyle (diet, body weight, and physical activity). Relative mtDNA-CN in peripheral blood leukocytes was measured by qPCR-based assay. RESULTS: We found a significant inverse association between ELIH and mtDNA-CN. In multivariable-adjusted linear models, absolute least squares means ± SDs of mtDNA-CN z score across ELIH quintiles in women were as follows: Q1: 0.14 ± 0.05; Q2: 0.04 ± 0.06; Q3: 0.008 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.06 ± 0.05 (P-trend = 0.006). Means ± SDs in men were as follows: Q1: 0.25 ± 0.09; Q2: 0.23 ± 0.09; Q3: 0.07 ± 0.09; Q4: 0.02 ± 0.09; and Q5: -0.04 ± 0.09 (P-trend = 0.007). Means ± SDs in all participants were as follows: Q1: 0.16 ± 0.05; Q2: 0.07 ± 0.05; Q3: 0.01 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.05 ± 0.05 (P-trend = 0.0004). CONCLUSIONS: Hyperinsulinemic lifestyles (i.e., higher ELIH) were associated with lower leukocyte mtDNA-CN among subjects without major diseases, suggesting that the difference in lifestyle insulinemic potential may be related to excessive oxidative stress damage.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , ADN Mitocondrial/genética , Hiperinsulinismo , Leucocitos , Estilo de Vida , Población Blanca/genética , Adulto , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Estados Unidos
13.
Am J Med Genet A ; 182(7): 1562-1571, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32426895

RESUMEN

We report on a 26-year-old male with extreme short stature, microcephaly, macroglossia, other dysmorphic features, severe intellectual disability, and a bone dysplasia. The patient had an extensive genetic and biochemical evaluation that was all normal or noninformative. Recently, the proband died following a period of not eating. He likely had a previously undescribed syndrome of unknown etiology.


Asunto(s)
Anomalías Múltiples/etiología , Enfermedades del Desarrollo Óseo/etiología , Enanismo/etiología , Adulto , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Cara/anomalías , Femenino , Retardo del Crecimiento Fetal , Humanos , Recién Nacido , Discapacidad Intelectual , Masculino , Microcefalia/etiología , Embarazo , Síndrome
14.
PLoS Genet ; 13(6): e1006825, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28640802

RESUMEN

Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD.


Asunto(s)
Metabolismo de los Hidratos de Carbono , Trastorno Peroxisomal/genética , Peroxisomas/metabolismo , Animales , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Glucosa/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mutación , Factor 2 de la Biogénesis del Peroxisoma , Peroxisomas/genética , Transcriptoma
15.
Am J Hum Genet ; 99(4): 831-845, 2016 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-27640307

RESUMEN

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.


Asunto(s)
Adenosina Trifosfatasas/genética , Alelos , Proteínas de la Membrana/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas Mitocondriales/genética , Mutación , Enfermedades del Sistema Nervioso/genética , ATPasas Asociadas con Actividades Celulares Diversas , Adulto , Animales , Axones/patología , Cardiomiopatías/genética , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/genética , Drosophila melanogaster/genética , Femenino , Fibroblastos , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Hipotonía Muscular/genética , Músculos/patología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Neuronas/patología , Atrofia Óptica/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Síndrome , Adulto Joven
16.
Am J Med Genet A ; 179(10): 2138-2143, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31290619

RESUMEN

Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.


Asunto(s)
Alelos , Discapacidad Intelectual/genética , Enfermedad de Leigh/genética , Mutación/genética , Convulsiones/genética , Niño , Preescolar , Transporte de Electrón , Complejo IV de Transporte de Electrones/genética , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Enfermedad de Leigh/diagnóstico por imagen , Masculino , Fenotipo , Convulsiones/diagnóstico por imagen
17.
Am J Med Genet A ; 179(12): 2357-2364, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31512387

RESUMEN

Coffin-Lowry syndrome (CLS) is a rare X-linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high-resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT-PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss-of-function mechanism. PCR analysis of the patients' cDNA detected a band greater than expected for an exon 4-10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next-generation sequencing and high-resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases.


Asunto(s)
Duplicación Cromosómica , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Hermanos , Niño , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , Linaje , Fenotipo
19.
PLoS Biol ; 13(7): e1002197, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26176594

RESUMEN

Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration--defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise.


Asunto(s)
Proteínas de Drosophila/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Células Fotorreceptoras de Invertebrados/efectos de la radiación , Enfermedades de la Retina/genética , Adenosina Trifosfato/biosíntesis , Animales , Citrato (si)-Sintasa/genética , Drosophila , Proteínas de Drosophila/metabolismo , Electrorretinografía , Endocitosis , Mitocondrias/genética , Proteínas Mitocondriales/metabolismo , Estrés Oxidativo , Complejo Piruvato Deshidrogenasa/genética , Complejo Piruvato Deshidrogenasa/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rodopsina/metabolismo , Visión Ocular
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA