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3.
Ideggyogy Sz ; 74(3-4): 135-138, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33938664

RESUMO

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal inherited metabolic disorder in which the ß-oxidation of the long chain fatty acids is defective. The clinical presentation may be in various forms; it presents itself in the severe form during neonatal and infantile periods and as the less severe myopathic form in the school age and adolescence. While the severity of the rhabdomyolysis attacks varies, occasionally the clinical course may be complicated with acute renal failure. Acylcarnitine analysis may help in the diagnosis of CPT II, but its normality does not indicate the absence of the disease. If there is strong suspicion, genetic analysis should be performed on the cases. In this article, we present a 15-year-old male patient who had two rhabdomyolysis attacks triggered by infection and starvation. Acylcarnitine analysis of the case was normal, CPT II deficiency was considered when the history was evaluated, and CPT II gene c.137A>G (p.Gln46Arg) homozygous novel pathogenic mutation was detected. CPT II deficiency is one of the most common causes of metabolic rhabdomyolysis in patients with recurrent episodes of rhabdomyolysis.


Assuntos
Erros Inatos do Metabolismo , Rabdomiólise , Adolescente , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Humanos , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Mutação , Rabdomiólise/genética
4.
J Psychiatr Res ; 138: 125-129, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33848968

RESUMO

Inborn errors of metabolism (IEMs) are a group of rare genetic disorders which, when emerging later in life, are often characterized by neuropsychiatric manifestations including psychosis. This study aimed to determine whether it would be useful to screen patients presenting with a psychotic disorder for IEMs by a single blood sample using Next Generation Sequencing (NGS), in order to detect rare, treatable causes of psychotic disorders. Blood was drawn from 60 patients with a psychotic disorder, with a duration of illness of less than 5 years. Blood samples were screened for 67 genes using NGS (Illumina® MiSeq sequencing technique). The results were compared to the human reference genome (GoNL, n = 498). The identified variants were classified according to the ACMG classification. For the psychotic patients, 6 variants of a likely pathogenic (class 4, n = 2) or pathogenic (class 5, n = 4) origin were found. As all variants were heterozygous, no patients were considered to be affected by an IEM. For the GoNL control group, 73 variants of a likely pathogenic (class 4, n = 31) or pathogenic (class 5, n = 42) origin were found. All of these found variants were heterozygous. Therefore, these individuals from the control group were considered to be a carrier only. Thus, no patients were identified to have an IEM as an underlying disease using this approach. However, NGS may be useful to detect variants of genes associated with IEMs in an enriched subgroup of psychotic patients.


Assuntos
Transtornos Mentais , Erros Inatos do Metabolismo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Programas de Rastreamento , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética
5.
Am J Hum Genet ; 108(4): 535-548, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798442

RESUMO

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.


Assuntos
Variação Genética/genética , Genética Médica , Genômica , Aprendizado de Máquina , Erros Inatos do Metabolismo/genética , Farmacogenética , Medicina de Precisão , Genoma Humano/genética , Humanos , Recém-Nascido
6.
Medicine (Baltimore) ; 100(17): e25697, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907148

RESUMO

RATIONALE: Transient infantile hypertriglyceridemia (HTGTI) is a rare autosomal recessive inherited disease caused by inactivating mutations in the glycerol-3-phosphate dehydrogenase 1 gene. To date, only a few patients have been reported worldwide. The symptoms of the affected individuals present a certain degree of transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis in early infancy. However, the clinical characteristics and pathogenesis of this disease are remain unclear. PATIENT CONCERNS: A one month and twenty-five days old girl was admitted to hospital because of persisted jaundice and hepatomegaly for fifty days. DIAGNOSE: The girl was diagnosed with HTGTI coincident with a noval mutation in glycerol-3-phosphate dehydrogenase 1. INTERVENTION: She was advised to take low-fat diet and supplement of medium-chain fatty acids. OUTCOMES: Her jaundice was gradually normal at the age of 4 months without any treatment, and hypertriglyceridemia were normal at the age of 13 months, but still had elevated transaminases and hepatic steatosis. LESSONS: Jaundice may be a novel phenotype in HTGTI. The report contributes to the expansion of HTGTI's gene mutation spectrum and its clinical manifestations.


Assuntos
Fígado Gorduroso , Glicerolfosfato Desidrogenase/genética , Hepatomegalia , Hipertrigliceridemia , Icterícia , Diagnóstico Diferencial , Dieta com Restrição de Gorduras/métodos , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/etiologia , Feminino , Testes Genéticos/métodos , Hepatomegalia/diagnóstico , Hepatomegalia/etiologia , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/genética , Lactente , Icterícia/diagnóstico , Icterícia/etiologia , Testes de Função Hepática , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Mutação , Transaminases/sangue
7.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799536

RESUMO

In the last decades, the therapeutic potential of hematopoietic stem cell transplantation (HSCT) has acquired a primary role in the management of a broad spectrum of diseases including cancer, hematologic conditions, immune system dysregulations, and inborn errors of metabolism. The different types of HSCT, autologous and allogeneic, include risks of severe complications including acute and chronic graft-versus-host disease (GvHD) complications, hepatic veno-occlusive disease, lung injury, and infections. Despite being a dangerous procedure, it improved patient survival. Hence, its use was extended to treat autoimmune diseases, metabolic disorders, malignant infantile disorders, and hereditary skeletal dysplasia. HSCT is performed to restore or treat various congenital conditions in which immunologic functions are compromised, for instance, by chemo- and radiotherapy, and involves the administration of hematopoietic stem cells (HSCs) in patients with depleted or dysfunctional bone marrow (BM). Since HSCs biology is tightly regulated by oxidative stress (OS), the control of reactive oxygen species (ROS) levels is important to maintain their self-renewal capacity. In quiescent HSCs, low ROS levels are essential for stemness maintenance; however, physiological ROS levels promote HSC proliferation and differentiation. High ROS levels are mainly involved in short-term repopulation, whereas low ROS levels are associated with long-term repopulating ability. In this review, we aim summarize the current state of knowledge about the role of ß3-adrenoreceptors (ß3-ARs) in regulating HSCs redox homeostasis. ß3-ARs play a major role in regulating stromal cell differentiation, and the antagonist SR59230A promotes differentiation of different progenitor cells in hematopoietic tumors, suggesting that ß3-ARs agonism and antagonism could be exploited for clinical benefit.


Assuntos
Doenças Hematológicas/genética , Células-Tronco Hematopoéticas/metabolismo , Doenças do Sistema Imunitário/genética , Neoplasias/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos beta 3/genética , Antagonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Regulação da Expressão Gênica , Doenças Hematológicas/tratamento farmacológico , Doenças Hematológicas/imunologia , Doenças Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/imunologia , Erros Inatos do Metabolismo/patologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Estresse Oxidativo , Propanolaminas/uso terapêutico , Espécies Reativas de Oxigênio/imunologia , Receptores Adrenérgicos beta 3/imunologia , Transplante Autólogo , Transplante Homólogo
8.
Methods Mol Biol ; 2280: 275-295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33751442

RESUMO

The aim of this short review chapter is to provide a brief summary of the relevance of riboflavin (Rf or vitamin B2) and its derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) for human neuromuscular bioenergetics.Therefore, as a completion of this book we would like to summarize what kind of human pathologies could derive from genetic disturbances of Rf transport, flavin cofactor synthesis and delivery to nascent apoflavoproteins, as well as by alteration of vitamin recycling during protein turnover.


Assuntos
Músculo Esquelético/metabolismo , Neurônios/metabolismo , Riboflavina/metabolismo , Metabolismo Energético , Mononucleotídeo de Flavina/metabolismo , Flavina-Adenina Dinucleotídeo/metabolismo , Predisposição Genética para Doença , Humanos , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo
9.
Am J Clin Nutr ; 113(5): 1157-1167, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33693455

RESUMO

BACKGROUND: The association of moderate hyperhomocysteinemia (HHcy) (15-30 µmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy. OBJECTIVE: We sought to evaluate the association of intermediate (30-100 µmol/L) and severe (>100 µmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes. METHODS: We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing. RESULTS: We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 µmol/L, 27% Hcy >50 µmol/L (44/165) and 3% Hcy >100 µmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6-60.4 compared with 12.1-28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after ∼4 y of follow-up. CONCLUSION: The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.


Assuntos
Doenças Cardiovasculares/etiologia , Deficiência de Ácido Fólico/complicações , Ácido Fólico/uso terapêutico , Hiper-Homocisteinemia/complicações , Erros Inatos do Metabolismo/sangue , Adulto , Pré-Escolar , Estudos Transversais , Feminino , Homocisteína/sangue , Homocisteína/metabolismo , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Ácido Metilmalônico/sangue , Ácido Metilmalônico/metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitamina B 12/sangue , Vitamina B 12/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(3): 271-274, 2021 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-33751540

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of a child with MEGDEL syndrome. METHODS: Clinical data of the child was reviewed. Peripheral blood samples of the child and his parents were collected. Mitochondrial genome and the whole exome of the child were analyzed by next-generation sequencing. Candidate variants and its origin were verified by Sanger sequencing and fluorescence quantitative PCR. RESULTS: The patient, a 2-year-and-6-month-old male, has featured hypoglycemia, mental and motor retardation with regression. Cranial MRI showed bilateral putamen damage suggestive of Leigh syndrome. Testing of urine organic acid indicated that the level of 3-methylpentenoic acid was slightly increased. Whole exome sequencing revealed that the child has harbored heterozygous deletion of exons 6 to 17 and c.307A>T nonsense variant of the SERAC1 gene, which were respectively inherited from his parents who were asymptomatic. Treatment with Levocarnitine, vitamin B1, vitamin B2, coenzyme Q10, baclofen and glucuronolactone resulted in improvement of sleep and mental state. CONCLUSION: A case of MEGDEL syndrome without deafness was diagnosed. Discovery of the nonsense mutation and large fragment deletion have enriched the spectrum of SERAC1 gene variants.


Assuntos
Perda Auditiva Neurossensorial , Doença de Leigh , Erros Inatos do Metabolismo , Pré-Escolar , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Biologia Molecular , Mutação
11.
Nat Commun ; 12(1): 964, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574263

RESUMO

Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e-7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.


Assuntos
Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/urina , Variação Genética , Genótipo , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Doenças Raras/genética , Sequenciamento Completo do Exoma
12.
Biochimie ; 183: 30-34, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33567294

RESUMO

Glycine conjugation is an important phase II reaction and represents a central detoxification pathway which is essential for the recycling of free coenzyme A. Only few sequence variants have been reported in the human GLYAT gene and only two studies have overexpressed the human protein in bacterial systems and partially characterized it. This has prompted us to study the wild-type enzyme and two sequence variants not only in the E. coli strain Origami 2(DE3), but also to overexpress GLYAT in HEK293 cells, a human-derived cell line. Following purification of the recombinant proteins from E. coli the wild-type GLYAT protein and sequence variants, p.(Gln61Leu) yielded decreased specific activity than the wild-type enzyme, while specific activity of p.(Asn156Ser) activity of the latter variant was somewhat increased. KM values were similar for the three forms of GLYAT overexpressed in bacteria and for the wild-type enzyme overexpressed in HEK293 cells. Localization studies demonstrated intramitochondrial localization of human wild-type GLYAT, conjugated with eGFP, in the HEK293 cells. As p.(Gln61Leu) does not only impair GLYAT activity in vitro, but is of high prevalence in a Caucasian Afrikaner cohort in South Africa, potential pharmacogenetic implications, warrant further studies of GLYAT.


Assuntos
Aciltransferases , Erros Inatos do Metabolismo , Mutação de Sentido Incorreto , Aciltransferases/química , Aciltransferases/genética , Aciltransferases/metabolismo , Substituição de Aminoácidos , Células HEK293 , Humanos , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/genética
13.
Clin Biochem ; 90: 66-72, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33539811

RESUMO

BACKGROUND: A small amount of methanol is produced endogenously in the human body but it is efficiently metabolized by alcohol dehydrogenase (ADH) and other enzymes, and the products eliminated without harm. In this study, we present a new entity of inborn error of methanol metabolism due to a mutation in the ADH1C gene coding for the γ subunit that is part of several ADH isoenzymes. RESULTS: This disorder was discovered in an 11.58-year-old boy. During one 9-month hospital admission, he had periods of 1-4 days during which he was comatose, and between these periods he was sometimes verbose and euphoric, and had ataxia, dysarthria. Following hemodialysis treatments, he became conscious and appeared healthy. Organ evaluations and his laboratory tests were normal. Toxicological evaluation of his blood showed a high methanol level [12.2 mg/dL (3.8 mmol/L), normal range up to 3.5 mg/dL (1.09 mmol/L) while the formaldehyde level was undetectable. The finding of liver function tests that were within normal limits, coupled with a normal eye examination and size of the liver, elevated blood methanol levels and an undetectable formaldehyde level, suggested ADH insufficiency. Adding zinc to the drug regimen 15 mg/daily dramatically reduced the patient's methanol level and alleviated the abnormal symptoms. When zinc supplementation was discontinued, the patient relapsed into a coma and hemodialysis was once again required. A homozygous mutation in ADH1C gene located at exon 3 was found, and both parents were heterozygous for this mutation. CONCLUSION: Accumulation of methanol due to mutation in ADH1C gene may result in drunkenness and ataxia, and leads to coma. This condition can be successfully treated with zinc supplementation as the cofactor of ADH.


Assuntos
Álcool Desidrogenase/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Metanol/sangue , Álcool Desidrogenase/metabolismo , Intoxicação Alcoólica/complicações , Ataxia/complicações , Criança , Coma/etiologia , Éxons/genética , Heterozigoto , Humanos , Fígado/metabolismo , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/terapia , Metanol/metabolismo , Mutação , Diálise Renal/métodos , Resultado do Tratamento , Zinco/administração & dosagem
14.
Biochimie ; 183: 18-29, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33421502

RESUMO

Pyridoxal 5'-phosphate (PLP), the active cofactor form of vitamin B6 is required by over 160 PLP-dependent (vitamin B6) enzymes serving diverse biological roles, such as carbohydrates, amino acids, hemes, and neurotransmitters metabolism. Three key enzymes, pyridoxal kinase (PL kinase), pyridoxine 5'-phosphate oxidase (PNPO), and phosphatases metabolize and supply PLP to PLP-dependent enzymes through the salvage pathway. In born errors in the salvage enzymes are known to cause inadequate levels of PLP in the cell, particularly in neuronal cells. The resulting PLP deficiency is known to cause or implicated in several pathologies, most notably seizures. One such disorder, PNPO-dependent neonatal epileptic encephalopathy (NEE) results from natural mutations in PNPO and leads to null or reduced enzymatic activity. NEE does not respond to conventional antiepileptic drugs but may respond to treatment with the B6 vitamers PLP and/or pyridoxine (PN). In born errors that lead to PLP deficiency in cells have also been reported in PL kinase, however, to date none has been associated with epilepsy or seizure. One such pathology is polyneuropathy that responds to PLP therapy. Phosphatase deficiency or hypophosphatasia disorder due to pathogenic mutations in alkaline phosphatase is known to cause seizures that respond to PN therapy. In this article, we review the biochemical features of in born errors pertaining to the salvage enzyme's deficiency that leads to NEE and other pathologies. We also present perspective on vitamin B6 treatment for these disorders, along with attempts to develop zebrafish model to study the NEE syndrome in vivo.


Assuntos
Encefalopatias Metabólicas , Hipóxia-Isquemia Encefálica , Erros Inatos do Metabolismo , Fosfotransferases (Aceptor do Grupo Álcool) , Fosfato de Piridoxal , Piridoxaminafosfato Oxidase/deficiência , Convulsões , Animais , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/metabolismo , Humanos , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/metabolismo , Recém-Nascido , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfato de Piridoxal/genética , Fosfato de Piridoxal/metabolismo , Piridoxaminafosfato Oxidase/genética , Piridoxaminafosfato Oxidase/metabolismo , Convulsões/genética , Convulsões/metabolismo
15.
JCI Insight ; 6(2)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33491665

RESUMO

To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their ß-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL-/-), fatty acid oxidation (Cpt2L-/-), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and ß-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.


Assuntos
Ácidos Graxos/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Triglicerídeos/metabolismo , Animais , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Progressão da Doença , Feminino , Hidrólise , Lipase/deficiência , Lipase/genética , Lipase/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Oxirredução
16.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33408250

RESUMO

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.


Assuntos
Imunidade/genética , Erros Inatos do Metabolismo/genética , Seleção Genética/genética , Genes Dominantes/genética , Genes Recessivos/genética , Variação Genética/genética , Variação Genética/imunologia , Humanos , Erros Inatos do Metabolismo/imunologia , Erros Inatos do Metabolismo/patologia
17.
Nat Genet ; 53(1): 54-64, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414548

RESUMO

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with ß-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.


Assuntos
Saúde , Metabolismo/genética , Diabetes Mellitus Tipo 2/genética , Oftalmopatias/genética , Frequência do Gene/genética , Loci Gênicos , Pleiotropia Genética , Genoma Humano , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Glicina/metabolismo , Humanos , Modelos Lineares , Análise da Randomização Mendeliana , Erros Inatos do Metabolismo/genética , Metaboloma/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Telangiectasia Retiniana/genética , Tamanho da Amostra , Serina/metabolismo
18.
Arterioscler Thromb Vasc Biol ; 41(1): 35-47, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33176451

RESUMO

Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.


Assuntos
Doenças da Aorta/genética , Artérias/metabolismo , Hipoplasia do Esmalte Dentário/genética , Hereditariedade , Erros Inatos do Metabolismo/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteogênese/genética , Osteoporose/genética , Calcificação Vascular/genética , Animais , Doenças da Aorta/complicações , Doenças da Aorta/metabolismo , Artérias/patologia , Hipoplasia do Esmalte Dentário/complicações , Hipoplasia do Esmalte Dentário/metabolismo , Doença de Gaucher/complicações , Doença de Gaucher/genética , Doença de Gaucher/metabolismo , Predisposição Genética para Doença , Humanos , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/metabolismo , Metacarpo/metabolismo , Doenças Musculares/complicações , Doenças Musculares/metabolismo , Odontodisplasia/complicações , Odontodisplasia/metabolismo , Osteoporose/complicações , Osteoporose/metabolismo , Fenótipo , Medição de Risco , Fatores de Risco , Calcificação Vascular/complicações , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
19.
Pediatr Clin North Am ; 68(1): 1-24, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33228926

RESUMO

Congenital bronchopulmonary malformations are relatively common and arise during various periods of morphogenesis. Although some are isolated or sporadic occurrences, others may result from single gene mutations or cytogenetic imbalances. Single gene mutations have been identified, which are etiologically related to primary pulmonary hypoplasia, lung segmentation defects as well as pulmonary vascular and lymphatic lesions. Functional defects in cystic fibrosis, primary ciliary dyskinesias, alpha-1-antitrypsin deficiency, and surfactant proteins caused by gene mutations may result in progressive pulmonary disease. This article provides an overview of pediatric pulmonary disease from a genetic perspective.


Assuntos
Pneumopatias/congênito , Pneumopatias/genética , Anormalidades do Sistema Respiratório/genética , Criança , Pré-Escolar , Doenças do Tecido Conjuntivo/congênito , Doenças do Tecido Conjuntivo/genética , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo/genética
20.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(5): 574-580, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33210482

RESUMO

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a family with combined oxidative phosphorylation deficiency 1 (COXPD-1). METHODS: The whole exome sequencing was performed in parents of the proband; and the genetic defects were verified by Sanger sequencing technology in the dried blood spot of the proband, the amniotic fluid sample of the little brother of proband, and the peripheral blood of the parents. RESULTS: Whole exome sequencing and Sanger validation showed compound heterozygous mutations of GFM1 gene c.688G>A(p.G230S) and c.1576C>T (p.R526X) in both the proband and her little brother, and the c.1576C>T of GFM1 variant was first reported. The two patients were died in early infancy, and presented with metabolic acidosis, high lactic acid, abnormal liver function, feeding difficulties, microcephaly, development retardation and epilepsy. CONCLUSIONS: GFM1 gene c.688G>A and c.1576C>T compound heterozygous mutations are the cause of this family of COXPD-1.


Assuntos
Encefalopatia Hepática , Erros Inatos do Metabolismo , Proteínas Mitocondriais , Fator G para Elongação de Peptídeos , Evolução Fatal , Feminino , Encefalopatia Hepática/genética , Humanos , Lactente , Masculino , Erros Inatos do Metabolismo/genética , Proteínas Mitocondriais/genética , Mutação , Fator G para Elongação de Peptídeos/genética , Sequenciamento Completo do Exoma
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