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1.
Hum Mutat ; 40(10): 1700-1712, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31058414

RESUMEN

3-Methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole-exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3-MGA-uria. A comprehensive analysis of the mitochondrial function was performed in fibroblasts of the patient to elucidate the molecular basis of the disease. TIMM50 protein was severely reduced in the patient fibroblasts, regardless of the normal mRNA levels, suggesting that the mutated residues might be important for TIMM50 protein stability. Severe morphological defects and ultrastructural abnormalities with aberrant mitochondrial cristae organization in muscle and fibroblasts were found. The levels of fully assembled OXPHOS complexes and supercomplexes were strongly reduced in fibroblasts from this patient. High-resolution respirometry demonstrated a significant reduction of the maximum respiratory capacity. A TIMM50-deficient HEK293T cell line that we generated using CRISPR/Cas9 mimicked the respiratory defect observed in the patient fibroblasts; notably, this defect was rescued by transfection with a plasmid encoding the TIMM50 wild-type protein. In summary, we demonstrated that TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity.


Asunto(s)
Proteínas de Transporte de Membrana/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación , Biomarcadores , Transporte de Electrón , Metabolismo Energético , Fibroblastos/metabolismo , Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Mitocondrias/ultraestructura , Enfermedades Mitocondriales/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Fenotipo , Transporte de Proteínas , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Secuenciación del Exoma
2.
EMBO Mol Med ; 16(1): 4-7, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38177529

RESUMEN

In the April issue of this Journal, Boffa and coworkers put forward a new therapeutic approach for Gyrate Atrophy of the Choroid and Retina (GACR; OMIM 258870) (Boffa et al, 2023). The authors propose to apply gene therapy to the liver for GACR, a metabolic disease primarily affecting eyesight due to retinal degeneration. Their vision is enthusiastically supported by a News and Views comment in the same issue (Seker Yilmaz and Gissen, 2023). However, based on disease pathology, patient's needs, ethical considerations, therapeutic developmental time lines, and current state of the art of gene therapy for liver and eye, we have a different view on this issue: We argue below that local treatment of the eye is the preferred option for GACR.


Asunto(s)
Atrofia Girata , Degeneración Retiniana , Humanos , Atrofia Girata/genética , Atrofia Girata/patología , Atrofia Girata/terapia , Retina/patología , Coroides , Degeneración Retiniana/terapia , Degeneración Retiniana/patología , Atrofia/patología
3.
J Clin Invest ; 131(8)2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33690217

RESUMEN

X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift toward monounsaturated fatty acids relieved toxicity. In human ALD fibroblasts, chloroquine also increased SCD1 levels and reduced saturated VLCFAs. Conversely, pharmacological inhibition of SCD1 expression led to an increase in saturated VLCFAs, and CRISPR knockout of scd1 in zebrafish mimicked the motor phenotype of ALD zebrafish. Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts, whereas monounsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated toward monounsaturated VLCFA and normalizing phospholipid profiles. Finally, Abcd1-/y mice receiving LXR agonist in their diet had VLCFA reductions in ALD-relevant tissues. These results suggest that metabolic rerouting of saturated to monounsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.


Asunto(s)
Adrenoleucodistrofia/enzimología , Cloroquina/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Receptores X del Hígado/agonistas , Estearoil-CoA Desaturasa/biosíntesis , Proteínas de Pez Cebra/metabolismo , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/metabolismo , Adrenoleucodistrofia/tratamiento farmacológico , Adrenoleucodistrofia/genética , Animales , Línea Celular , Ácidos Grasos/metabolismo , Humanos , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Ratones , Ratones Noqueados , Mutación , Estearoil-CoA Desaturasa/genética , Pez Cebra , Proteínas de Pez Cebra/genética
4.
EMBO Mol Med ; 8(2): 139-54, 2016 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-26697888

RESUMEN

Barth syndrome (BTHS) is a cardiomyopathy caused by the loss of tafazzin, a mitochondrial acyltransferase involved in the maturation of the glycerophospholipid cardiolipin. It has remained enigmatic as to why a systemic loss of cardiolipin leads to cardiomyopathy. Using a genetic ablation of tafazzin function in the BTHS mouse model, we identified severe structural changes in respiratory chain supercomplexes at a pre-onset stage of the disease. This reorganization of supercomplexes was specific to cardiac tissue and could be recapitulated in cardiomyocytes derived from BTHS patients. Moreover, our analyses demonstrate a cardiac-specific loss of succinate dehydrogenase (SDH), an enzyme linking the respiratory chain with the tricarboxylic acid cycle. As a similar defect of SDH is apparent in patient cell-derived cardiomyocytes, we conclude that these defects represent a molecular basis for the cardiac pathology in Barth syndrome.


Asunto(s)
Síndrome de Barth/patología , Succinato Deshidrogenasa/deficiencia , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ratones
5.
Orphanet J Rare Dis ; 8: 57, 2013 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-23570448

RESUMEN

BACKGROUND: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia. METHODS: We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. RESULTS: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. CONCLUSIONS: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.


Asunto(s)
Hiperlisinemias/genética , Secuencia de Bases , Western Blotting , Línea Celular , Estudios de Cohortes , Hibridación Genómica Comparativa , Cartilla de ADN , ADN Complementario/genética , Humanos , Hiperlisinemias/sangre , Hiperlisinemias/fisiopatología , Mutación , Sacaropina Deshidrogenasas/genética
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