Abstract:
:Mutations in GDAP1 lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease, CMT), indicating that GDAP1 is essential for the viability of cells in the peripheral nervous system. GDAP1 contains domains characteristic of glutathione-S-transferases (GSTs), is located in the outer mitochondrial membrane and induces fragmentation of mitochondria. We found GDAP1 upregulated in neuronal HT22 cells selected for resistance against oxidative stress. GDAP1 over-expression protected against oxidative stress caused by depletion of the intracellular antioxidant glutathione (GHS) and against effectors of GHS depletion that affect the mitochondrial membrane integrity like truncated BH3-interacting domain death agonist and 12/15-lipoxygenase. Gdap1 knockdown, in contrast, increased the susceptibility of motor neuron-like NSC34 cells against GHS depletion. Over-expression of wild-type GDAP1, but not of GDAP1 with recessively inherited mutations that cause disease and reduce fission activity, increased the total cellular GHS content and the mitochondrial membrane potential up to a level where it apparently limits mitochondrial respiration, leading to reduced mitochondrial Ca(2+) uptake and superoxide production. Fibroblasts from autosomal-recessive CMT4A patients had reduced GDAP1 levels, reduced GHS concentration and a reduced mitochondrial membrane potential. Thus, our results suggest that the potential GST GDAP1 is implicated in the control of the cellular GHS content and mitochondrial activity, suggesting an involvement of oxidative stress in the pathogenesis of CMT4A.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Noack R,Frede S,Albrecht P,Henke N,Pfeiffer A,Knoll K,Dehmel T,Meyer Zu Hörste G,Stettner M,Kieseier BC,Summer H,Golz S,Kochanski A,Wiedau-Pazos M,Arnold S,Lewerenz J,Methner Adoi
10.1093/hmg/ddr450subject
Has Abstractpub_date
2012-01-01 00:00:00pages
150-62issue
1eissn
0964-6906issn
1460-2083pii
ddr450journal_volume
21pub_type
杂志文章abstract::Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.7.1117
更新日期:1994-07-01 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::Slow-channel syndrome (SCS) is a congenital myasthenic disorder caused by point mutations in subunits of skeletal muscle acetylcholine receptor leading to Ca(2+) overload and degeneration of the postsynaptic membrane, nuclei and mitochondria of the neuromuscular junction (NMJ). In both SCS muscle biopsies and transgen...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt397
更新日期:2014-01-01 00:00:00
abstract::X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr512
更新日期:2012-02-15 00:00:00
abstract::To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt293
更新日期:2013-11-15 00:00:00
abstract::Fragile X syndrome is the most frequent cause of heritable mental retardation. Most patients have a mutation in the 5' untranslated region of the FMR1 gene, consisting of the amplification of a polymorphic (CGG)nrepeat sequence, and cytogenetically express the folate-sensitive fragile site FRAXA in Xq27.3. Fragile X p...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.1.109
更新日期:1998-01-01 00:00:00
abstract::We have identified a rare mutation (T-45C) in the low density lipoprotein (LDL)-receptor gene in a Welsh patient with a clinical diagnosis of heterozygous familial hypercholesterolaemia (FH). The mutation is in the proximal Sp1 binding site in repeat 3 of the 42 bp region of the promoter required for sterol-dependent ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.11.2125
更新日期:1995-11-01 00:00:00
abstract::Andersen's syndrome (AS) is a rare and dominantly inherited pathology, linked to the inwardly rectifying potassium channel Kir2.1. AS patients exhibit a triad of symptoms that include periodic paralysis, cardiac dysrhythmia and bone malformations. Some progress has been made in understanding the contribution of the Ki...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu462
更新日期:2015-01-15 00:00:00
abstract::Parkin E3 ubiquitin-ligase activity and its role in mitochondria homeostasis are thought to play a role in Parkinson's disease (PD). We now report that AF-6 is a novel parkin interacting protein that modulates parkin ubiquitin-ligase activity and mitochondrial roles. Parkin interacts with the AF-6 PDZ region through i...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt058
更新日期:2013-05-15 00:00:00
abstract::Skin color is a highly heritable human trait, and global variation in skin pigmentation has been shaped by natural selection, migration, and admixture. Ethnically diverse African populations harbor extremely high levels of genetic and phenotypic diversity, and skin pigmentation varies widely across Africa. Recent geno...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddab007
更新日期:2021-01-12 00:00:00
abstract::The gene which is defective in Duchenne muscular dystrophy (DMD) is the largest known gene. The product of the gene in muscle, dystrophin, is a 427 kDa protein. The same gene encodes at least six additional products: two non-muscle dystrophin isoforms transcribed from promoters located in the 5'-end region of the gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.4.581
更新日期:1998-04-01 00:00:00
abstract::Convergent extension (CE) is a fundamental morphogenetic mechanism that underlies numerous processes in vertebrate development, and its disruption can lead to human congenital disorders such as neural tube closure defects. The dynamic, oriented cell intercalation during CE is regulated by a group of core proteins iden...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx095
更新日期:2017-06-01 00:00:00
abstract::Loss-of-function mutations of the X-chromosome gene UPF3B cause male neurodevelopmental disorders (NDDs) via largely unknown mechanisms. We investigated initially by interrogating a novel synonymous UPF3B variant in a male with absent speech. In silico and functional studies using cell lines derived from this individu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa151
更新日期:2020-08-29 00:00:00
abstract::Fragile X syndrome, the most common form of inherited mental retardation, is caused by the loss of the fragile X mental retardation protein (FMRP). FMRP is a ubiquitously expressed, multi-domain RNA-binding protein, but its in vivo function remains poorly understood. Recent studies have shown that FMRP participates in...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds307
更新日期:2012-11-01 00:00:00
abstract::The electrocardiogram has several advantages in detecting cardiac arrhythmia-it is readily available, noninvasive and cost-efficient. Recent genome-wide association studies have identified single-nucleotide polymorphisms that are associated with electrocardiogram measures. We performed a genome-wide association study ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu374
更新日期:2014-12-15 00:00:00
abstract::Ocular albinism type 1 (OA1) is an X-linked recessive disorder characterized by a major impairment of visual acuity, nystagmus, strabismus, photophobia and retinal hypopigmentation. From the analysis of patients carrying deletions and translocations involving the distal short arm of the X chromosome (Xp22.3) we have i...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.3.373
更新日期:1995-03-01 00:00:00
abstract::Potocki-Lupski syndrome (PTLS; MIM #610883), characterized by neurobehavioral abnormalities, intellectual disability and congenital anomalies, is caused by a 3.7-Mb duplication in 17p11.2. Neurobehavioral studies determined that ∼70-90% of PTLS subjects tested positive for autism or autism spectrum disorder (ASD). We ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds124
更新日期:2012-07-15 00:00:00
abstract::The clearest example of genomic imprinting in humans comes from studies of the Angelman (AS) and Prader-Willi (PWS) syndromes. Although these are clinically distinct disorders, both typically result from a loss of the same chromosomal region, 15q11-q13. AS usually results from either a maternal deletion of this region...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.9.1377
更新日期:1993-09-01 00:00:00
abstract::Lysosomes, melanosomes and platelet-dense granules are abnormal in the mouse hypopigmentation mutant pearl. The beta3A subunit of the AP-3 adaptor complex, which likely regulates protein trafficking in the trans - Golgi network/endosomal compartments, was identified as a candidate for the pearl gene by a positional/ca...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.2.323
更新日期:1999-02-01 00:00:00
abstract::Mutations in mitochondrial DNA (mtDNA) are associated with a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNAs is an important determinant of both the onset and the severity of the disease phenotype, but the mechanisms controlling mtDNA segregation remain poorly understood. To investig...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi293
更新日期:2005-09-01 00:00:00
abstract::Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of N...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.24.2751
更新日期:2001-11-15 00:00:00
abstract::Recent studies with tiling arrays have revealed more genomic transcription than previously anticipated. Whole new groups of non-coding transcripts (NCTs) have been detected. Some of these NCTs, including miRNAs, can regulate gene expression. To date, most known NCTs studied have been relatively short, but several impo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm336
更新日期:2008-03-01 00:00:00
abstract::A gene's transcriptional output is the combined product of two inputs: diffusible factors in the cellular milieu acting in trans, and chromatin state acting in cis. Here, we describe a strategy for dissecting the relative contribution of cis versus trans mechanisms to gene regulation. Referred to as trans complementat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn409
更新日期:2009-03-01 00:00:00
abstract::Heterozygosity for mutations (N88S and P90L) in the N-glycosylation site of seipin/BSCL2 is associated with the autosomal dominant motor neuron diseases, spastic paraplegia 17 and distal hereditary motor neuropathy type V, referred to as 'seipinopathies'. Previous in vitro studies have shown that seipinopathy-linked m...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr304
更新日期:2011-10-01 00:00:00
abstract::A 1.5 Mb duplication within 17p11.2 is the major mutation causing both autosomal dominant and sporadic Charcot-Marie-Tooth disease type 1A (CMT1A). An independent origin for the mutation in each family has been postulated. The proposed genetic mechanism causing the CMT1A duplication is unequal nonsister chromatid exch...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.12.2031
更新日期:1993-12-01 00:00:00
abstract::Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of a CAG repeat in a gene coding for a protein of unknown function. We have raised a polyclonal antibody against a 12 amino acid peptide (residues 2110-2121 of human huntingtin) which specifically recognises huntingtin on West...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.4.481
更新日期:1996-04-01 00:00:00
abstract::Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF be...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv257
更新日期:2015-10-01 00:00:00
abstract::Proteolytic fragmentation of polyglutamine-expanded ataxin-3 is a concomitant and modifier of the molecular pathogenesis of Machado-Joseph disease (MJD), the most common autosomal dominant cerebellar ataxia. Calpains, a group of calcium-dependent cysteine proteases, are important mediators of ataxin-3 cleavage and imp...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa010
更新日期:2020-04-15 00:00:00
abstract::Steroid 11 beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol. Severely affected patients carry mutations in the CYB11B1 gene that destroy enzymatic activity. Such patients have signs of androgen excess and usually have hyperten...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.11.1829
更新日期:1997-10-01 00:00:00
abstract::Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw023
更新日期:2016-04-01 00:00:00