Abstract:
:The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia. Increasing evidence underlines the pathogenetic role of oxidative stress in this disease. We generated an in vitro cellular model of regulated human frataxin overexpression. We identified, by differential display technique, the mitogen activated protein kinase kinase 4 mRNA down regulation in frataxin overexpressing cells. We studied the stress kinases pathway in this cellular model and in fibroblasts from FRDA patients. Frataxin overexpression reduced c-Jun N-terminal kinase phosphorylation. Furthermore, exposure of FRDA fibroblasts to several forms of environmental stress caused an up regulation of phospho-JNK and phospho-c-Jun. To understand if this susceptibility results in cell death, we have investigated the involvement of caspases. A significantly higher activation of caspase-9 was observed in FRDA versus control fibroblasts after serum-withdrawal. Our findings suggest the presence, in FRDA patient cells, of a 'hyperactive' stress signaling pathway. The role of frataxin in FRDA pathogenesis could be explained, at least in part, by this hyperactivity.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Pianese L,Busino L,De Biase I,De Cristofaro T,Lo Casale MS,Giuliano P,Monticelli A,Turano M,Criscuolo C,Filla A,Varrone S,Cocozza Sdoi
10.1093/hmg/11.23.2989subject
Has Abstractpub_date
2002-11-01 00:00:00pages
2989-96issue
23eissn
0964-6906issn
1460-2083journal_volume
11pub_type
杂志文章abstract::Spastic paraplegia 35 (SPG35) (OMIM: 612319) or fatty acid hydroxylase-associated neurodegeneration (FAHN) is caused by deficiency of fatty acid 2-hydroxylase (FA2H). This enzyme synthesizes sphingolipids containing 2-hydroxylated fatty acids, which are particularly abundant in myelin. Fa2h-deficient (Fa2h-/-) mice de...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa246
更新日期:2021-01-21 00:00:00
abstract::Lysosomal neuraminidase (sialidase) occurs in a high molecular weight complex with the glycosidase beta-galactosidase and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Association of the enzyme with PPCA is crucial for its correct targeting and lysosomal activation. In man two genetically distinct...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.2.313
更新日期:1998-02-01 00:00:00
abstract::Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn156
更新日期:2008-08-15 00:00:00
abstract::Congenital nephrotic syndrome of the Finnish type (CNF or NPHS1) is an autosomal recessive kidney disorder resulting in severe proteinurea and renal dysfunction. Although the disease occurs predominantly in the Finnish population, many cases in other populations have also been reported. The disease gene (NPHS1) encode...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.23.2637
更新日期:2001-11-01 00:00:00
abstract::Advances in information technology (IT) hardware in the last decade have led to the advent of small connected devices broadly referred to as the Internet of Things (IoT). The IoT and its subcategory of wearable devices (wearables) both have the potential to greatly impact biomedical research. This focused review cover...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy092
更新日期:2018-05-01 00:00:00
abstract::Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically dive...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw358
更新日期:2016-12-15 00:00:00
abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major path...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx214
更新日期:2017-09-01 00:00:00
abstract::Ankylosing spondylitis (AS) remains difficult to diagnose before irreversible damage to sacroiliac joint is noticeable. Circulating microRNAs have demonstrated to serve as diagnostic tools for several human diseases. Here, we analysed plasma microRNAs to identify potential AS biomarkers. Higher expression levels of mi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy008
更新日期:2018-03-01 00:00:00
abstract::We have shown previously that AWT1 and WT1-AS are functionally imprinted in human kidney. In the adult kidney, expression of both transcripts is restricted to the paternal allele, with the silent maternal allele retaining methylation at the WT1 antisense regulatory region (WT1 ARR). Here, we report characterization of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl478
更新日期:2007-02-01 00:00:00
abstract::Chediak-Higashi syndrome is an autosomal recessive, immune deficiency disorder of human (CHS) and mouse (beige, bg) that is characterized by abnormal intracellular protein transport to, and from, the lysosome. Recent reports have described the identification of homologous genes that are mutated in human CHS and bg mic...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.7.1091
更新日期:1997-07-01 00:00:00
abstract::Deficiency of the dysferlin protein presents as two major clinical phenotypes: limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. The size of the dysferlin cDNA prevents...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq065
更新日期:2010-05-15 00:00:00
abstract::The human POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase gamma (pol gamma). Mutations in pol gamma are associated with a spectrum of disease phenotypes including autosomal dominant and recessive forms of progressive external ophthalmoplegia, spino-cerebellar ataxia and epilepsy, and Alpers-Hut...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl219
更新日期:2006-10-01 00:00:00
abstract::Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was pe...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl447
更新日期:2007-02-01 00:00:00
abstract::Protein engineering is a means to optimize protein therapeutics developed for the treatment of so far incurable diseases including cancers and genetic disorders. Here we report on an engineering approach in which we successfully increased the catalytic rate constant of an enzyme that is presently evaluated in enzyme r...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz020
更新日期:2019-06-01 00:00:00
abstract::The gene responsible for Huntington disease has been localized to a 2.5 million base pair (Mb) region between the loci D4S10 and D4S168 on the short arm of chromosome 4. As part of a strategy to clone the HD gene on the basis of its chromosomal location, we isolated genomic DNA from the HD region as a set of overlappi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/1.3.149
更新日期:1992-06-01 00:00:00
abstract::Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by an expanded (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The toxic RNA transcripts produced from the mutant allele alter the function of RNA-binding proteins leading to the functio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt419
更新日期:2014-01-15 00:00:00
abstract::The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. Mutations in this gene are responsible for four recessively inherited chondrodysplasias that include diastrophic dysplasia, multiple epip...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.14.1485
更新日期:2001-07-01 00:00:00
abstract::A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw094
更新日期:2016-06-01 00:00:00
abstract::Nineteen Wnt ligands and 10 Frizzled (Fz) receptors mediate multiple distinct cellular events during neuronal development. However, their precise roles in cell-type specification and organogenesis are poorly delineated because of overlapping functions and expression profiles. Here, we have explored the role of two clo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr616
更新日期:2012-04-15 00:00:00
abstract::Muscle-eye-brain disease (MEB), an autosomal recessive disorder prevalent in Finland, is characterized by congenital muscular dystrophy, brain malformation and ocular abnormalities. Since the MEB phenotype overlaps substantially with those of Fukuyama-type congenital muscular dystrophy (FCMD) and Walker-Warburg syndro...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg043
更新日期:2003-03-01 00:00:00
abstract::Human cytidine deaminase APOBEC3G and the virion infectivity factor (vif) of the human immunodeficiency virus (HIV) are a pair of antagonistic molecules. In the absence of vif, APOBEC3G induces a high rate of dC to dU mutations in the nascent reverse transcripts of HIV that leads to the degradation of the HIV genome. ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh183
更新日期:2004-08-15 00:00:00
abstract::The high affinity receptor for IgE (Fc epsilon RI) has a central role in mast cell degranulation and IgE mediated allergy. A systematic search through the coding regions of the beta subunit of Fc epsilon RI (Fc epsilon RI-beta) has identified a novel coding polymorphism in exon seven. An adenine to guanine substitutio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.7.959
更新日期:1996-07-01 00:00:00
abstract::Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a prema...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy445
更新日期:2019-05-01 00:00:00
abstract::While several high-resolution recombination maps exist for European-descent populations, the recombination landscape of African populations remains relatively understudied. Given that there is high genetic divergence among groups in Africa, it is possible that recombination hotspots also diverge significantly. Both li...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddab020
更新日期:2021-01-14 00:00:00
abstract::Slow channel congenital myasthenic syndrome (SCCMS) is a disorder of the neuromuscular synapse caused by dominantly inherited missense mutations in genes that encode the muscle acetylcholine receptor (AChR) subunits. Here we investigate the potential of post-transcriptional gene silencing using RNA interference (RNAi)...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg280
更新日期:2003-10-15 00:00:00
abstract::Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the unde...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy310
更新日期:2018-12-15 00:00:00
abstract::Transposable elements (TEs) are major sources of new exons in higher eukaryotes. Almost half of the human genome is derived from TEs, and many types of TEs have the potential to exonize. In this work, we conducted a large-scale analysis of human exons derived from mammalian-wide interspersed repeats (MIRs), a class of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp152
更新日期:2009-06-15 00:00:00
abstract::In our efforts to identify new loci responsible for non-syndromic autosomal recessive forms of deafness, DFNB loci, we have pursued the analysis of large consanguineous affected families living in geographically isolated areas. Here, we report on the study of a Lebanese family comprising nine members presenting with a...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.3.409
更新日期:1999-03-01 00:00:00
abstract::Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular disease that affects the aorta, carotid, coronary and pulmonary arteries. Previous molecular genetic data have led to the hypothesis that SVAS results from mutations in the elastin gene, ELN. In these studies, the disease phenotype was linked to...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.7.1021
更新日期:1997-07-01 00:00:00
abstract::Melanomas contain high frequencies of tumorigenic cells and their tumorigenic capacity resides in several distinct subpopulations within melanoma. Since their metastatic potential is linked to their ability to recruit lymphatic vessels, we aimed at identifying lymphangiogenic subpopulations by comparative in vitro ana...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds171
更新日期:2012-08-01 00:00:00