Abstract:
:We report here the case of a young male who started to show verbal fluency disturbance, clumsiness and gait anomalies at the age of 3.5years and presented bilateral striatal necrosis. Clinically, the diagnosis was compatible with Leigh syndrome but the underlying molecular defect remained elusive even after exome analysis using autosomal/X-linked recessive or de novo models. Dosage of respiratory chain activity on fibroblasts, but not in muscle, underlined a deficit in complex I. Re-analysis of heterozygous probably pathogenic variants, inherited from one healthy parent, identified the p.Ala178Pro in NDUFAF6, a complex I assembly factor. RNA analysis showed an almost mono-allelic expression of the mutated allele in blood and fibroblasts and puromycin treatment on cultured fibroblasts did not lead to the rescue of the maternal allele expression, not supporting the involvement of nonsense-mediated RNA decay mechanism. Complementation assay underlined a recovery of complex I activity after transduction of the wild-type gene. Since the second mutation was not detected and promoter methylation analysis resulted normal, we hypothesized a non-exonic event in the maternal allele affecting a regulatory element that, in conjunction with the paternal mutation, leads to the autosomal recessive disorder and the different allele expression in various tissues. This paper confirms NDUFAF6 as a genuine morbid gene and proposes the coupling of exome sequencing with mRNA analysis as a method useful for enhancing the exome sequencing detection rate when the simple application of classical inheritance models fails.
journal_name
Mol Genet Metabjournal_title
Molecular genetics and metabolismauthors
Bianciardi L,Imperatore V,Fernandez-Vizarra E,Lopomo A,Falabella M,Furini S,Galluzzi P,Grosso S,Zeviani M,Renieri A,Mari F,Frullanti Edoi
10.1016/j.ymgme.2016.09.001subject
Has Abstractpub_date
2016-11-01 00:00:00pages
214-222issue
3eissn
1096-7192issn
1096-7206pii
S1096-7192(16)30203-7journal_volume
119pub_type
杂志文章abstract::Alterations in the ferrochelatase gene (FECH) are the basis of the phenotypic expressions in erythropoietic protoporphyria. The phenotype is due to the presence of a mutation in the FECH gene associated in trans to the c.315-48 T > C variant in the intron 3. The latter is able to increase the physiological quota of al...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2018.06.005
更新日期:2018-08-01 00:00:00
abstract::To elucidate the basis of mucopolysaccharidosis type VI (MPS VI) from the point of view of enzyme structure, we built structural models of mutant N-acetylgalactosamine-4-sulfatase (4S) resulting from 34 missense mutations (17 severe and 17 attenuated), and analyzed the influence of each amino acid replacement on the s...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2007.11.017
更新日期:2008-04-01 00:00:00
abstract::This study describes the phenotype/genotype analyses of 56 probands with a juvenile onset, some of which had atypical features of neuronal ceroid lipofuscinosis, collected at the New York State Institute for Basic Research (IBR). In this group, we found probands with abundant curvilinear profiles in lysosomal storage ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1999.2814
更新日期:1999-04-01 00:00:00
abstract::The only known Japanese child with biotinidase deficiency was identified by newborn screening in Japan. He has 10.8% of mean normal serum biotinyl-hydrolase activity and trace biotinyl-transferase activity. The mutation results in 16% of normal cross-reacting material in serum with antibody to purified normal biotinid...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1998.2706
更新日期:1998-06-01 00:00:00
abstract::Cardiac malformations (CVMs) are a leading cause of infant morbidity and mortality. CVMs are particularly prevalent when the developing fetus is exposed to high levels of phenylalanine in-utero in mothers with Phenylketonuria. Yet, elucidating the underlying molecular mechanism leading to CVMs has proven difficult. In...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2018.09.003
更新日期:2019-01-01 00:00:00
abstract::Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabo...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2017.06.014
更新日期:2017-08-01 00:00:00
abstract::The primary treatment for phenylketonuria (PKU) is a low phenylalanine diet together with an amino acid-based, phenylalanine-free formula. Thus, PKU patients tend to consume a diet enriched in carbohydrates which could predispose to obesity. Studies in the 1980s and 1990s demonstrated that school-age phenylketonuria (...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.07.006
更新日期:2012-09-01 00:00:00
abstract::Ruminant placental lactogens (PLs) are structurally related to prolactins (PRLs) and growth hormones (GHs) and are secreted by placentae. Ruminant PLs are unusual in their capacity to bind and activate PRL and GH receptors (Rs) from other species. The present minireview summarizes several works showing that unlike in ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1006/mgme.2002.3303
更新日期:2002-03-01 00:00:00
abstract::Mevalonate kinase deficiency is a rare autosomal recessively inherited organic aciduria with a complex multi-systemic phenotype. We describe two deceased patients with clinically severe mevalonate kinase (MK) deficiency confirmed by MK mutation analysis. The phenotype in our patients ranged from neonatal hydrops in th...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.10.019
更新日期:2012-12-01 00:00:00
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journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2019.03.003
更新日期:2019-04-01 00:00:00
abstract::Increased glucose metabolism through the hexosamine pathway may result in insulin resistance, impaired insulin secretion, and diabetic nephropathy. We hypothesized that variants of GFPT1 encoding glutamine-fructose-6-phosphate amidotransferase, the rate limiting enzyme in this pathway, could increase GFPT1 gene expres...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2004.05.004
更新日期:2004-08-01 00:00:00
abstract:BACKGROUND:Propionic acidemia (PA) is an organic aciduria caused by inherited deficiency of propionyl-CoA carboxylase. Left ventricular dysfunction and QT prolongation may lead to life-threatening complications. Systematic analyses of cardiac phenotypes, in particular effects of specific cardiac therapies, are scarce. ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2020.02.004
更新日期:2020-05-01 00:00:00
abstract::A common variant (rs4712652) adjacent to the prolactin gene was recently associated with obesity using a genome-wide association study. The aim of this study was to replicate the association between rs4712652 and obesity and further examine if rs4712652 is associated with fat percentage and adiponectin levels in a pop...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.08.017
更新日期:2011-01-01 00:00:00
abstract:BACKGROUND:Flow-injection MS/MS methods for elevated acylcarnitines are routinely performed in most newborn screening and biochemical genetics laboratories; however this technique cannot distinguish between isobaric compounds; therefore, chromatographic separation is required to quantitate isomers for differential diag...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2010.05.012
更新日期:2010-09-01 00:00:00
abstract:BACKGROUND:While enzyme replacement therapy (ERT) has been shown to improve endurance and joint mobility for patients with mucopolysaccharidoses (MPS) I, II, IVA and VI, the impact of ERT on cardiac abnormalities remains uncertain. METHODS:Medical records and echocardiograms of 28 Taiwanese MPS patients (9 with MPS I,...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2016.02.003
更新日期:2016-04-01 00:00:00
abstract::The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic beta-cell genes including IPF1. We hypothesized that sequence variants of FOXO1A contribute to the observed defects ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2006.01.003
更新日期:2006-06-01 00:00:00
abstract::Oxidative metabolism of glucose is regulated by pyruvate dehydrogenase (PDH) that can be inhibited by isoforms of PDH kinase (PDK). Recently, increased PDK activity has been implicated in the pathogenesis of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) in obese subjects. Using quantitative RT...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1998.2748
更新日期:1998-10-01 00:00:00
abstract::The tissue specificity of mitochondrial diseases is poorly understood. Recently, tissue-specific quantitative differences of the components of the mitochondrial translation system have been found to correlate with disease presentation in fatal hepatopathy caused by mutations in mitochondrial translation factor EFG1. M...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2007.02.006
更新日期:2007-06-01 00:00:00
abstract::Human reproductive function is regulated mainly by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Mutations of the human LH/ chorionic gonadotropin receptor (LHR) and the FSH receptor (FSHR) leading to either constitutive activation or inactivation of the receptors have been identified. All activatin...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1006/mgme.1997.2650
更新日期:1998-02-01 00:00:00
abstract::We describe a novel mitochondrial ND2 mutation (T4681C) in a patient presenting with Leigh Syndrome. Biochemical analyses revealed a low isolated complex I activity in patient's fibroblasts, blood and skeletal muscle. Mutant transmitochondrial cybrid clones retained the specific complex I defect, demonstrating the mit...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2006.08.003
更新日期:2007-01-01 00:00:00
abstract::In Duchenne muscular dystrophy (DMD), identification of one nonsense mutation in the DMD gene has been considered an endpoint of genetic diagnosis. Here, we identified two closely spaced nonsense mutations in the DMD gene. In a Malaysian DMD patient two nonsense mutations (p.234S>X and p.249Q>X, respectively) were ide...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.04.002
更新日期:2011-07-01 00:00:00
abstract::Infantile hepatopathies are life-threatening liver disorders that manifest in the first few months of life. We report on a consanguineous Irish Traveller family that includes six individuals presenting with acute liver failure in the first few months of life. Additional symptoms include anaemia, renal tubulopathy, dev...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.04.017
更新日期:2012-07-01 00:00:00
abstract::Mutations in the arylsulfatase E gene, located on the X chromosome, have been shown to cause chondrodysplasia punctata (CDP). A substitution of arginine with serine at amino acid 12 (R12S) was identified in a patient with typical features of mild symmetrical CDP including mild mental retardation. The proband was insti...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.1999.2935
更新日期:1999-12-01 00:00:00
abstract::Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder mainly caused by defects in the steroid 21-hydroxylase (CYP21) gene. For reliable and accurate mutation detection in the CYP21 gene it is important to separate the CYP21 gene from the highly homologous CYP21P pseudogene. For this, several di...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1006/mgme.2000.3023
更新日期:2000-08-01 00:00:00
abstract::Sanfilippo disease (MPS IIIA) is an autosomal recessive lysosomal storage disorder resulting from sulfamidase deficiency, which is characterized by severe neurological impairment. Various tissues of MPS IIIA mice accumulate undegraded glycosaminoglycans and mimic the human neurodegenerative disorder, and are an excell...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2011.01.015
更新日期:2011-05-01 00:00:00
abstract::Anophthalmia and microphthalmia (A/M) are significant eye defects because they can have profound effects on visual acuity. A/M is associated with non-ocular abnormalities in an estimated 33-95% of cases and around 25% of patients have an underlying genetic syndrome that is diagnosable. Syndrome recognition is importan...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章,评审
doi:10.1016/j.ymgme.2011.09.029
更新日期:2011-12-01 00:00:00
abstract::Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by deficiency of the lysosomal enzyme β-glucuronidase (GUS), leading to accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) effectively clears GAG storage in the viscera. Recent studies showed that a chemically modified ...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2012.07.002
更新日期:2012-09-01 00:00:00
abstract:BACKGROUND:The long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU. METHODS:We investigated 35 patients with early-treated classical PKU aged 2...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2018.12.011
更新日期:2019-03-01 00:00:00
abstract::Mucolipidosis type II is an autosomal recessive lysosomal storage disease caused by N-acetylglucosamine-1-phosphotransferese deficiency. We report here pathological findings of an autopsy case of mucolipidosis type II. The patient was an 8-year-old boy with mucolipidosis type II and was complicated with hypertrophic c...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2014.05.001
更新日期:2014-07-01 00:00:00
abstract:BACKGROUND:There is current expansion of newborn screening (NBS) programs to include lysosomal storage disorders because of the availability of treatments that produce an optimal clinical outcome when started early in life. OBJECTIVE:To evaluate the performance of a multiplex-tandem mass spectrometry (MS/MS) enzymatic...
journal_title:Molecular genetics and metabolism
pub_type: 杂志文章
doi:10.1016/j.ymgme.2016.05.015
更新日期:2016-08-01 00:00:00