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1.
Nat Med ; 28(11): 2321-2332, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36357675

RESUMO

Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.


Assuntos
Erros Inatos do Metabolismo , Metaboloma , Humanos , Metaboloma/genética , Metabolômica , Plasma/metabolismo , Fenótipo , Erros Inatos do Metabolismo/genética , Proteínas de Membrana/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo
2.
Int J Mol Sci ; 23(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36361642

RESUMO

Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE, IDUA, PTS, ASS1 and OTC, all affecting the splicing process, and two located in the promoters of IDUA and PTS, thus affecting these genes' expression. All the new variants were subjected to functional analysis to verify their pathogenic effects. This work underscores how the combination of different omics technologies and functional analysis can solve elusive cases in clinical practice.


Assuntos
Doença da Urina de Xarope de Bordo , Erros Inatos do Metabolismo , Recém-Nascido , Humanos , Exoma , Sequenciamento Completo do Exoma , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Triagem Neonatal
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(10): 1085-1088, 2022 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-36184088

RESUMO

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with infantile hepatitis syndrome. METHODS: Genes associated with liver diseases subjected to high-throughput sequencing. Candidate variants were validated by Sanger sequencing of the proband and his parents. The pathogenicity of the variants was analyzed through bioinformatic analysis. RESULTS: High-throughput sequencing revealed that the proband has harbored c.182T>C (p.F61S) and c.293C>T (p.P98L) variants of the MPV17 gene, which were verified by Sanger sequencing to be inherited from his parents. The variant c.182T>C (p.F61S) was unreported previously and predicted to be likely pathogenic by bioinformatic analysis. CONCLUSION: The proband was caused by the compound heterozygous variations of MPV17 gene including c.182T>C (p.F61S) and c.293C>T (p.P98L). Discovery of the novel variant has enriched the spectrum of pathogenic variants of the MPV17 gene.


Assuntos
Testes Genéticos , Erros Inatos do Metabolismo , China , DNA Mitocondrial/genética , Feminino , Humanos , Proteínas de Membrana/genética , Erros Inatos do Metabolismo/genética , Proteínas Mitocondriais/genética , Mutação , Linhagem , Gravidez , Diagnóstico Pré-Natal , Síndrome
4.
Pediatr Clin North Am ; 69(5): 1003-1016, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36207093

RESUMO

Metabolic disorders or inborn errors of metabolism (IEMs) can have a wide range of neurodevelopmental and behavioral presentations. These can vary with age and/or management or stressors from common childhood/intercurrent illnesses/procedures/interventions. Collaborative care models such as multidisciplinary metabolic clinics or colocated models with behavioral health clinics and metabolic clinics in the same location can be valuable resources in improving long-term outcomes in patients with IEM. Psychologists' expertise using behavioral interventions, screening, or adaptive/cognitive measures can help with diagnosis, treatment adherence, school performance, family support, community resources, transition to adolescence and young adulthood using health belief concepts to improve outcomes.


Assuntos
Doenças Metabólicas , Erros Inatos do Metabolismo , Adolescente , Adulto , Criança , Humanos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/terapia , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Adulto Jovem
6.
Mol Genet Metab ; 137(3): 292-300, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36252453

RESUMO

DNA polymorphic markers and self-defined ethnicity groupings are used to group individuals with shared ancient geographic ancestry. Here we studied whether ancestral relationships between individuals could be identified from metabolic screening data reported by the California newborn screening (NBS) program. NBS data includes 41 blood metabolites measured by tandem mass spectrometry from singleton babies in 17 parent-reported ethnicity groupings. Ethnicity-associated differences identified for 71% of NBS metabolites (29 of 41, Cohen's d > 0.5) showed larger differences in blood levels of acylcarnitines than of amino acids (P < 1e-4). A metabolic distance measure, developed to compare ethnic groupings based on metabolic differences, showed low positive correlation with genetic and ancient geographic distances between the groups' ancestral world populations. Several outlier group pairs were identified with larger genetic and smaller metabolic distances (Black versus White) or with smaller genetic and larger metabolic distances (Chinese versus Japanese) indicating the influence of genetic and of environmental factors on metabolism. Using machine learning, comparison of metabolic profiles between all pairs of ethnic groupings distinguished individuals with larger genetic distance (Black versus Chinese, AUC = 0.96), while genetically more similar individuals could not be separated metabolically (Hispanic versus Native American, AUC = 0.51). Additionally, we identified metabolites informative for inferring metabolic ancestry in individuals from genetically similar populations, which included biomarkers for inborn metabolic disorders (C10:1, C12:1, C3, C5OH, Leucine-Isoleucine). This work sheds new light on metabolic differences in healthy newborns in diverse populations, which could have implications for improving genetic disease screening.


Assuntos
Erros Inatos do Metabolismo , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem/métodos , Aminoácidos/genética , Biomarcadores
7.
Rev Mal Respir ; 39(9): 758-777, 2022 Nov.
Artigo em Francês | MEDLINE | ID: mdl-36229356

RESUMO

Inborn metabolic diseases or inborn errors of metabolism comprise a large number of rare and heterogeneous genetic diseases categorized in several subgroups depending on their pathophysiologic mechanisms. In this review, we focus on different metabolic diseases with respiratory symptoms in adults: lysosomal glycosphingolipidoses such as acid sphingomyelinase deficiency (Niemann-Pick types A and B disease), Gaucher, Fabry, Pompe diseases and mucopolysaccharidoses in general. We also address classical homocystinuria, which is a monogenic vascular disease, Hermansky-Pudlak syndrome, which is associated with disorders in the lysosomal-related-organelles, and lysinuric protein intolerance, which is due to an amino-acid transporter defect. Presentation and prognosis of these diseases are highly heterogeneous, and respiratory impairment may be central and prognostic. Many are primarily pediatric, and diagnoses are often delivered during childhood. Improved pediatric management has enabled better prognosis and new phenotype of the diseases in the adulthood. Some others can be diagnosed during adulthood. While some diseases call for specific, specialized treatment, all necessitate systematic multidisciplinary management. It is of paramount importance that a pneumologist be familiar with these phenotypes, most of which can benefit from early diagnosis and early therapeutic management with dedicated innovative treatments.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Doenças Metabólicas , Erros Inatos do Metabolismo , Humanos , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Fenótipo
8.
Sci Rep ; 12(1): 16668, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36198723

RESUMO

Epidemiological literature indicates that women are less susceptible to type II diabetes (T2D) than males. The general consensus is that estrogen is protective, whereas its deficiency in post-menopause is associated with adiposity and impaired insulin sensitivity. However, epidemiological data suggests that males are more prone to developing T2D, and at a lower BMI, compared to females during post-menopausal years; suggesting that another factor, other than estrogen, protects females. We proposed to determine if adiponectin (APN) serves as this protective factor. An initial experiment was performed in which gonadally intact male and female mice were fed either a purified low-fat diet (LFD) or high-fat diet (HFD) (40% kcals from fat) for 16 weeks. An additional group of HFD ovariectomy (OVX) mice were included to assess estrogen deficiency's impact on obesity. Body composition, adipose tissue inflammation, ectopic lipid accumulation as well as glucose metabolism and insulin resistance were assessed. In corroboration with previous data, estrogen deficiency (OVX) exacerbated HFD-induced obesity in female mice. However, despite a higher body fat percentage and a similar degree of hepatic and skeletal muscle lipid accumulation, female OVX HFD-fed mice exhibited enhanced insulin sensitivity relative to HFD-fed males. Therefore, a subsequent HFD experiment was performed utilizing male and female (both gonadally intact and OVX) APN deficient mice (APN-/-) and wildtype littermates to determine if APN is the factor which protects OVX females from the similar degree of metabolic dysfunction as males in the setting of obesity. Indirect calorimetry was used to determine observed phenotype differences. APN deficiency limited adiposity and mitigated HFD-induced insulin resistance and adipose tissue inflammation in gonadally intact male and female, but not in OVX mice. Using indirect calorimetry, we uncovered that slight, but non-statistically significant differences in food intake and energy expenditure leading to a net difference in energy balance likely explain the reduced body weight exhibited by male APN-deficient mice. In conclusion, congenital APN deficiency is protective against obesity development in gonadally intact mice, however, in the setting of estrogen deficiency (OVX) this is not true. These findings suggest that gonadal status dictates the protective effects of congenital APN deficiency in the setting of HFD-induced obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adiponectina/deficiência , Animais , Dieta Hiperlipídica/efeitos adversos , Estrogênios/metabolismo , Feminino , Glucose/metabolismo , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Lipídeos , Masculino , Erros Inatos do Metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Ovariectomia
10.
Biomolecules ; 12(9)2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36139147

RESUMO

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance.


Assuntos
Citocromo P-450 CYP3A , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides , Fator de Necrose Tumoral alfa , Aminoácidos/genética , Citocromo P-450 CYP3A/genética , Glucocorticoides , Humanos , Erros Inatos do Metabolismo , Mutação de Sentido Incorreto , Receptores de Glucocorticoides/genética , Fator de Necrose Tumoral alfa/genética
11.
Methods Mol Biol ; 2546: 55-64, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36127578

RESUMO

Analysis of clinically relevant amino acids using ion exchange chromatography coupled to photometric/fluorescent detection has been an indispensable component in the detection of inborn errors of metabolism for six decades. Detection of amino acids using mass spectrometry offers advantages in speed and analytic specificity. Employing methanol extraction and controlled butylation, C8 reversed-phase chromatography, and MS/MS detection, 32 amino acids are quantified in 20 min with clinically appropriate imprecision in plasma, urine, and cerebrospinal fluid (CSF). Quantitation is linear to 2500 µM, and limits of detection are at least 1.0 µM. Important isobaric amino acids are distinguished by chromatography or by unique patterns of fragmentation following collision-induced dissociation (CID). The technique employs commercially available reagents and may be expanded and customized for specific clinical or research settings.


Assuntos
Aminoácidos , Erros Inatos do Metabolismo , Aminoácidos/química , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Erros Inatos do Metabolismo/diagnóstico , Metanol , Espectrometria de Massas em Tandem/métodos
12.
Methods Mol Biol ; 2546: 335-350, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36127602

RESUMO

A patient suspected of an inborn error of metabolism will commonly have urine organic acid analysis performed as part of their workup. The traditional urine organic acid method involves extraction of the acidic fraction from urine samples using an organic solvent, derivatization of extracted compounds, and identification using gas chromatography-mass spectrometry (GC/MS). Unfortunately, the extraction step results in the loss of many neutral and positively charged compounds which may be of interest to metabolic physicians and biochemical geneticists. By replacing the traditional extraction step with an enzymatic treatment of the sample with urease, an abundance of organic molecules is available for separation and quantification by GC/MS. The urease method is a useful adjunct to newborn screening follow-up, and it has the additional benefit of being able to identify many classes of biochemical compounds, such as amino acids, acylglycines, neurotransmitters, and carbohydrates. This method describes the urease treatment, derivatization, and the organic acids and other biochemical metabolites that can be identified.


Assuntos
Erros Inatos do Metabolismo , Urease , Ácidos , Aminas , Aminoácidos , Carboidratos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/metabolismo , Solventes
13.
Mol Genet Metab ; 137(1-2): 213-222, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36155185

RESUMO

Metabolic myopathies are characterized by the deficiency or dysfunction of essential metabolites or fuels to generate energy for muscle contraction; they most commonly manifest with neuromuscular symptoms due to impaired muscle development or functioning. We have summarized associations of signs and symptoms in 358 inherited metabolic diseases presenting with myopathies. This represents the tenth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.


Assuntos
Doenças Metabólicas , Erros Inatos do Metabolismo , Doenças Musculares , Humanos , Doenças Musculares/metabolismo , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Doenças Metabólicas/genética
14.
J Hum Genet ; 67(12): 691-699, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36064591

RESUMO

PURPOSE: To describe a novel DNA2 variant contributing to defects in mtDNA maintenance and mtDNA depletion syndrome (MDS), and the clinical and histological findings associated with this variation. METHODS: Herein, we describe the case of a patient who presented with hearing loss and myopathy, given the family history of similar findings in the father, was evaluated by sequencing of the deafness gene panel, mitochondrial genome, and the exome. Furthermore, tissue staining, mtDNA copy number detection, mtDNA sequencing, and long-range polymerase chain reaction tests were also conducted on the muscle biopsy specimen. In vitro experiments, including analyses of the mtDNA copy number; levels of ATP, ATPase, and reactive oxygen species (ROS); and the membrane potential, were performed. RESULTS: The DNA2 heterozygous truncating variant c. 2368C > T (p.Q790X) was identified and verified as the cause of an mtDNA copy number decrement in both functional experiments and muscle tissue analyses. These changes were accompanied by reductions in ATP, ATPase, and ROS levels. CONCLUSION: The DNA2 variant was a likely cause of MDS in this patient. These findings expand the mutational spectrum of MDS and improve our understanding of the functions of DNA2 by revealing its novel role in mtDNA maintenance.


Assuntos
DNA Mitocondrial , Erros Inatos do Metabolismo , Humanos , DNA Mitocondrial/genética , Espécies Reativas de Oxigênio , Mutação , Adenosina Trifosfatases/genética , Trifosfato de Adenosina , DNA Helicases/genética
16.
Int Rev Cell Mol Biol ; 372: 55-96, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36064267

RESUMO

Inborn errors of metabolism (IEM) encompass a group of monogenic diseases affecting both pediatric and adult populations and currently lack effective treatments. Some IEM such as familial hypercholesterolemia or X-linked protoporphyria are caused by gain of function mutations, while others are characterized by an impaired protein function, causing a metabolic pathway blockage. Pathophysiology classification includes intoxication, storage and energy-related metabolic disorders. Factors specific to each disease trigger acute metabolic decompensations. IEM require prompt and effective care, since therapeutic delay has been associated with the development of fatal events including severe metabolic acidosis, hyperammonemia, cerebral edema, and death. Rapid expression of therapeutic proteins can be achieved hours after the administration of messenger RNAs (mRNA), representing an etiological solution for acute decompensations. mRNA-based therapy relies on modified RNAs with enhanced stability and translatability into therapeutic proteins. The proteins produced in the ribosomes can be targeted to specific intracellular compartments, the cell membrane, or be secreted. Non-immunogenic lipid nanoparticle formulations have been optimized to prevent RNA degradation and to allow safe repetitive administrations depending on the disease physiopathology and clinical status of the patients, thus, mRNA could be also an effective chronic treatment for IEM. Given that the liver plays a key role in most of metabolic pathways or can be used as bioreactor for excretable proteins, this review focuses on the preclinical and clinical evidence that supports the implementation of mRNA technology as a promising personalized strategy for liver metabolic disorders such as acute intermittent porphyria, ornithine transcarbamylase deficiency or glycogen storage disease.


Assuntos
Hepatopatias , Doenças Metabólicas , Erros Inatos do Metabolismo , Nanopartículas , Adulto , Criança , Humanos , Lipossomos , Doenças Metabólicas/complicações , Doenças Metabólicas/genética , Doenças Metabólicas/terapia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
17.
Medicina (B Aires) ; 82 Suppl 3: 40-45, 2022 Aug 30.
Artigo em Espanhol | MEDLINE | ID: mdl-36054856

RESUMO

Inborn errors of metabolism constitute a growing group of rare diseases with usual neurological impact. Heterogeneous in clinical and biochemical aspects, its diagnosis and treatment are difficult. Advances in its knowledge, in diagnostic methods and in its treatments, highlight the importance of a timely diagnosis, the gateway to access to early medical intervention. The neuropediatrician's suspicion in different clinical situations is very relevant. This article aims to be a practical contribution to facilitate their recognition.


Los errores congénitos del metabolismo constituyen un grupo creciente de enfermedades poco frecuentes con habitual impacto neurológico. Heterogéneas en el aspecto clínico y bioquímico, su diagnóstico y terapéutica son dificultosos. Los avances en su conocimiento, en los métodos diagnósticos y en sus tratamientos, ponen de relevancia lo importante de un diagnóstico oportuno, puerta del acceso a la intervención médica temprana. Es muy relevante la sospecha del neuropediatra ante diferentes situaciones clínicas. El presente artículo pretende ser un aporte práctico para facilitar su reconocimiento.


Assuntos
Doenças Metabólicas , Erros Inatos do Metabolismo , Humanos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia
18.
Bull Cancer ; 109(10): 1082-1087, 2022 Oct.
Artigo em Francês | MEDLINE | ID: mdl-35934543

RESUMO

Gastrointestinal stromal tumors (GIST) are rare digestive tumors. Activating KIT mutations are the most common molecular alteration in these patients, identified in approximately 70 % of cases, followed by PDGFRA mutations (10-15 %), of which the D842V mutation accounts for most cases. Succinate dehydrogenase (SDH) deficiency and alterations involving NF1, BRAFV600E, RAS or NTRK genes are rare molecular subgroups. In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively. Two new compounds have recently been evaluated in patients with advanced GIST. Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments. Avapritinib is now the recommended first-line treatment in this subgroup and may represent an additional option, whose place remains to be clarified, in pre-treated patients without D842V mutations. Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.


Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Antineoplásicos/uso terapêutico , Complexo II de Transporte de Elétrons/deficiência , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Erros Inatos do Metabolismo , Doenças Mitocondriais , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Succinato Desidrogenase/genética , Sunitinibe/uso terapêutico
19.
Nephrology (Carlton) ; 27(10): 810-814, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35960161

RESUMO

BCS1L pathogenic variants cause widely different clinical phenotypes. Disease phenotypes can be as mild as Björnstad syndrome, characterized by pili torti (abnormal flat twisted hair shafts) and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death. BCS1L pathogenic variants are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving renal and hepatic pathologies, hypotonia, and developmental delays. So far, all patients with GRACILE syndrome carry a homozygous p.Ser78Gly variant in BCS1L gene by reviewing articles. A 24-day-old boy presented with typical clinical phenotype of GRACILE syndrome. The Whole Exome Sequencing confirmed that the patient had a missense variant (c.245C > T, p.Ser82Leu) and a small deletion (c.231_232delCA, p. Ser78Cysfs*9) in BCS1L gene inherited from his father and mother separately, he died at 5 months of age. We reported a patient with GRACILE syndrome and identified two novel variants in BCS1L gene. Our study expands the mutational spectrum of BCS1L gene associated with GRACILE syndrome and will be beneficial for genetic diagnosis.


Assuntos
Acidose Láctica , Colestase , ATPases Associadas a Diversas Atividades Celulares/genética , Acidose Láctica/genética , Colestase/diagnóstico , Colestase/genética , Complexo III da Cadeia de Transporte de Elétrons , Retardo do Crescimento Fetal , Hemossiderose , Humanos , Masculino , Erros Inatos do Metabolismo , Doenças Mitocondriais/congênito , Aminoacidúrias Renais
20.
J Mol Graph Model ; 117: 108288, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35961217

RESUMO

Dihydropyrimidinase (DHP) is an enzyme that catabolizes the degradation of pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil. DHP deficiency triggers various clinical symptoms and increases the risk of fluoropyrimidine drug toxicity. Various pathogenic variants of DHP cause DHP deficiency, and their catalytic activities have been well studied. However, the three-dimensional structures of DHP variants have not been clarified. In this study, we investigated the effects of mutations on DHP structures using the molecular dynamics simulations. Simulations of the wild type and 10 variants were performed and compared. In the T68R, D81G, G278D, and L337P variants, the flexibilities of structures related to the interaction for oligomer formation increased in comparison with those of the wild type. W117R, T343A, and R412 M mutations affected the structures of stereochemistry gate loops or the substrate-binding pocket. The three-dimensional structures of W360R and G435R variants were suggested to collapse. On the other hand, only slight structural changes were observed in the R181W variant, whose experimentally observed activity was similar to that of the wild type. The computational results are expected to clarify the relationship between clinical mutations and structural effects of drug-metabolizing enzymes.


Assuntos
Amidoidrolases , Simulação de Dinâmica Molecular , Amidoidrolases/química , Fluoruracila , Erros Inatos do Metabolismo
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