Abstract:
:Mutations in the DKC1 gene are responsible for causing the bone marrow failure syndrome, dyskeratosis congenita (DKC; OMIM 305000). The majority of mutations identified to date are missense mutations and are clustered in exons 3, 4 and 11. It is predicted that the corresponding protein dyskerin is a nucleolar phosphoprotein which functions in both pseudo-uridylation and cleavage of precursor rRNA. Dyskerin contains multiple putative nuclear localization signals (NLSs) at the N-terminus (KKHKKKKERKS) and C-terminus [KRKR(X)(17)KKEKKKSKKDKKAK(X)(17)-KKKKKKKKAKEVELVSE]. By fusing dyskerin with the enhanced green fluorescent protein (EGFP) and by following a time course of expression in mammalian cell lines, we showed that full-length dyskerin initially localizes to the nucleoplasm and subsequently accumulates in the nucleoli. A co-localization to the coiled bodies was observed in some cells where dyskerin-EGFP had translocated to the nucleoli. Analysis of a series of mutant constructs indicated that whereas the most C-terminal lysine-rich clusters [KKEKKKS-KKDKKAK(X)(17)KKKKKKKKAKEVELVSE] influence the rate of nucleoplasmic and nucleolar accumulation, the KRKR sequence is primarily responsible for the nuclear import. Nucleolar localization was maintained when either the N- or C-terminal motifs were mutated, but not when all NLSs were removed. We conclude that the intranuclear localization of dyskerin is accomplished by the synergistic effect of a number of NLSs and that the nucleolar localization signals are contained within the NLSs. Further, examination of dyskerin-EGFP fusions mimicking mutations detected in patients indicated that the intracellular mislocalization of dyskerin is unlikely to cause DKC.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Heiss NS,Girod A,Salowsky R,Wiemann S,Pepperkok R,Poustka Adoi
10.1093/hmg/8.13.2515subject
Has Abstractpub_date
1999-12-01 00:00:00pages
2515-24issue
13eissn
0964-6906issn
1460-2083pii
ddc279journal_volume
8pub_type
杂志文章abstract::KDM6B/JMJD3 is a histone H3 lysine demethylase with an important gene regulatory role in development and physiology. Here, we show that human JMJD3 expression is induced by the active vitamin D metabolite 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and that JMJD3 modulates the gene regulatory action of this hormone....
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr399
更新日期:2011-12-01 00:00:00
abstract::Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disorder linked to ectopic expression of DUX4. However, DUX4 is notoriously difficult to detect in FSHD muscle cells, while DUX4 target gene expression is an inconsistent biomarker for FSHD skeletal muscle biopsies, displaying efficacy only on pathologicall...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa053
更新日期:2020-08-11 00:00:00
abstract::Spliceosomal Uridine-rich small ribonucleo protein (U snRNP) assembly is an active process mediated by the macromolecular survival motor neuron (SMN) complex. This complex contains the SMN protein and six additional proteins, named Gemin2-7, according to their localization to nuclear structures termed gems. Here, we p...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi343
更新日期:2005-10-15 00:00:00
abstract::Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on pre-mRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor transformer2-beta1 (tra2-beta1) via a phylogenetically conserved RVDF se...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm284
更新日期:2008-01-01 00:00:00
abstract::Alterations in mitochondrial DNA (mtDNA) and consequent loss of mitochondrial function underlie the mitochondrial theory of aging. In this study, we systematically analyzed the mtDNA control region somatic mutation pattern in 2864 single hematopoietic stem cells (HSCs) and progenitors, isolated by flow cytometry sorti...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl457
更新日期:2007-02-01 00:00:00
abstract::The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97-1250 triplets in lymphoblastoid cell lines passaged 20-39 times. Southern analyses revealed 18 events of s...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.13.2425
更新日期:1999-12-01 00:00:00
abstract::In humans, the concerted action of at least 13 different peroxisomal PEX proteins is needed for proper peroxisome biogenesis. Mutations in any of these PEX genes can lead to lethal neurometabolic disorders of the Zellweger syndrome spectrum (ZSS). Previously, we identified the W313G mutation located within the SH3 dom...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt238
更新日期:2013-10-01 00:00:00
abstract::Glial cell line-derived neurotrophic factor (GDNF), a distant member of the TGF-beta superfamily, is a survival factor for various neurons, making it a potential therapeutic agent for neurodegenerative disorders. Here we present the genomic structure and characterization of the promoter of the human GDNF (hGDNF) gene....
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.12.1873
更新日期:1998-11-01 00:00:00
abstract::Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in the huntingtin protein. Full-length huntingtin is thought to be a predominant HEAT repeat alpha-solenoid, implying a role as a facilitator of macromolecular complexes. Here we have investigated huntingtin's domain structure an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp524
更新日期:2010-02-15 00:00:00
abstract::Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone diseas...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx178
更新日期:2017-08-15 00:00:00
abstract::Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, preclinical and clinical studies revealed a limited therapeutic time window and systemic aspects of the disease. This raises a fundamental question of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa146
更新日期:2020-09-29 00:00:00
abstract::T-box transcription factor, TBX1, is the major candidate gene for 22q11.2 deletion syndrome (DiGeorge/ Velo-cardio-facial syndrome) characterized by facial defects, thymus hypoplasia, cardiovascular anomalies and cleft palates. Here, we report that the loss of Tbx1 in mouse (Tbx1(-/-)) results in skeletal abnormalitie...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu458
更新日期:2015-01-15 00:00:00
abstract::Immunoglobulins play an essential part in the immune system, and immunoglobulin deficiencies can have profound medical consequences. The genetic control and regulation of the immunoglobulin response is therefore of interest. Previous investigations have identified a number of loci influencing total and specific IgE le...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.1.27
更新日期:1998-01-01 00:00:00
abstract::Autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by mutations in the Aquaporin-2 (AQP2) gene. Analysis of a new family with dominant NDI revealed a single nucleotide deletion (727deltaG) in one AQP2 allele, which encoded ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.7.779
更新日期:2002-04-01 00:00:00
abstract::A single-base substitution in the coding region of the androgen receptor (AR) gene caused complete androgen insensitivity in a patient with 46,XY karyotype. The mutation was a T-to-G transition in exon 6 and changed the codon 807 from ATG (methionine) to AGG (arginine) in the hormone-binding domain of the protein. The...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.11.1809
更新日期:1993-11-01 00:00:00
abstract::PRESENILIN1 (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including produ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt448
更新日期:2014-02-01 00:00:00
abstract::Mitochondrial dysfunction and oxidative stress are central to the molecular pathology of many human diseases. Riboflavin responsive multiple acyl-CoA dehydrogenation deficiency (RR-MADD) is in most cases caused by variations in the gene coding for electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Curr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu146
更新日期:2014-08-15 00:00:00
abstract::The quakingviable mouse (qkv) is a spontaneous recessive mouse mutant with a deletion of approximately 1.1 Mb in the proximal region of chromosome 17. The deletion affects the expression of three genes; quaking (Qk), Parkin-coregulated gene (Pacrg) and parkin (Park2). The resulting phenotype, which includes dysmyelina...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq031
更新日期:2010-04-15 00:00:00
abstract::Transcobalamin II (TC II) deficiency is a rare autosomal recessive disease leading to cobalamin (Cbl; Vitamin B12) deficiency characterized by failure to thrive, megaloblastic anemia, impaired immunodefence and neurological manifestations. By means of Southern blotting and sequence analysis of TC II cDNA amplified fro...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.10.1835
更新日期:1994-10-01 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::Pathological modifications in the microtubule-associated protein Tau is a common characteristic observed in different neurological diseases, suggesting that analogous metabolic pathways might be similarly affected during neurodegeneration. To identify these molecules and mechanisms, we utilized Drosophila models of hu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu393
更新日期:2014-12-20 00:00:00
abstract::We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demonstrate that TOPORS...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq543
更新日期:2011-03-01 00:00:00
abstract::Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularizatio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz159
更新日期:2019-10-15 00:00:00
abstract::The human genome is often portrayed as consisting of three sequence types, each distinguished by their mode of evolution. Purifying selection is estimated to act on 2.5-5.0% of the genome, whereas virtually all remaining sequence is considered to have evolved neutrally and to be devoid of functionality. The third mode...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddl182
更新日期:2006-10-15 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::Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterati...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr381
更新日期:2011-12-01 00:00:00
abstract::The parent of origin-dependent expression of the IGF2 and H19 genes is controlled by the imprinting centre 1 (IC1) consisting in a methylation-sensitive chromatin insulator. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith-Wiedemann syndrome (BWS). T...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn031
更新日期:2008-05-15 00:00:00
abstract::Adoptively transferred antigen-specific T cells that recognize tumor antigens through their native receptors have many potential benefits as treatment for virus-associated diseases and malignancies, due to their ability to selectively recognize tumor antigens, expand and persist to provide long-term protection. Infusi...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddv270
更新日期:2015-10-15 00:00:00
abstract::The childhood motor neuron disease spinal muscular atrophy (SMA) results from reduced expression of the survival motor neuron (SMN) gene. Previous studies using in vitro model systems and lower organisms have suggested that low levels of Smn protein disrupt prenatal developmental processes in lower motor neurons, infl...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp506
更新日期:2010-02-01 00:00:00
abstract::X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr536
更新日期:2012-03-01 00:00:00