Abstract:
:Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian target of rapamycin and disabling brain lesions. These lesions contain misplaced neurons enriched in hypoxia-inducible factor 1a (HIF1a). However, the relationship between TSC1/2 and HIF1a and the function of HIF1a in TSC neurons remain unexplored. Here, we examine the degree of HIF1a activity and its function in newborn Tsc1(null) neurons in a mouse model of TSC. Using single cell electroporation in the neurogenic subventricular zone (SVZ) of neonatal mice, we deleted Tsc1 and generated olfactory lesions containing misplaced Tsc1(null) neurons as previously reported. These newborn neurons displayed elevated HIF1a-mediated transcriptional activity when compared with Tsc1 heterozygote neurons and a marked resistance to cell death induced by a HIF1a antagonist. Electroporation of Hif1a targeting short hairpin RNA (shRNA) or dominant negative HIF1a constructs resulted in 80-90% loss of Tsc1(null) newborn neurons although sparing SVZ stem cells. Consistent with this later finding, induction of Hif1a shRNA expression during synaptic integration thus bypassing neuron production also resulted in newborn neuron death. Collectively, these results suggest that HIF1a acts as a molecular determinant of newborn neuron survival and that its TSC1-dependent up-regulation gave Tsc1(null) neurons a survival advantage, despite their misplacement in a novel microenvironment.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Feliciano DM,Zhang S,Quon JL,Bordey Adoi
10.1093/hmg/ddt018subject
Has Abstractpub_date
2013-05-01 00:00:00pages
1725-34issue
9eissn
0964-6906issn
1460-2083pii
ddt018journal_volume
22pub_type
杂志文章abstract::Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we sho...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp195
更新日期:2009-07-15 00:00:00
abstract::Huntington's disease is neurodegenerative disorder caused by a polyglutamine expansion in the N-terminal region of the huntingtin protein (N17). Here, we analysed the relative contribution of each phosphorylatable residue in the N17 region (T3, S13 and S16) towards huntingtin exon 1 (HTTex1) oligomerization, aggregati...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx260
更新日期:2017-10-01 00:00:00
abstract::Gaucher disease, a prevalent lysosomal storage disease (LSD), is caused by insufficient activity of acid β-glucosidase (GCase) and the resultant glucosylceramide (GC)/glucosylsphingosine (GS) accumulation in visceral organs (Type 1) and the central nervous system (Types 2 and 3). Recent clinical and genetic studies im...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu105
更新日期:2014-08-01 00:00:00
abstract::Keratins K6 and K16 are expressed in suprabasal interfollicular epidermis in wound healing and other pathological conditions associated with hyperproliferation, such as psoriasis and are induced when keratinocytes are cultured in vitro. However, these keratins are also constitutively expressed in normal suprabasal muc...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.10.1875
更新日期:1995-10-01 00:00:00
abstract::The first steps of ether lipid biosynthesis are exclusively localized to peroxisomes and hence some peroxisomal disorders are characterized by a severe deficiency of plasmalogens, the main ether lipids in humans. Here we report on gene defects of plasmalogen biosynthesis, chromosomal localization of the corresponding ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.2.127
更新日期:2001-01-15 00:00:00
abstract::The size of the (CAG)n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is ass...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.7.1137
更新日期:1995-07-01 00:00:00
abstract::Fragile X syndrome, a common cause of intellectual disability and autism, is due to mutational silencing of the FMR1 gene leading to the absence of its gene product, fragile X mental retardation protein (FMRP). FMRP is a selective RNA binding protein owing to two central K-homology domains and a C-terminal arginine-gl...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu586
更新日期:2015-03-15 00:00:00
abstract::Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the first exon of the HD gene, which results in a toxic polyglutamine stretch within huntingtin, the protein it encodes. Understanding the normal function of this essential protein is vital to u...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl467
更新日期:2007-02-15 00:00:00
abstract::Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recru...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg074
更新日期:2003-04-01 00:00:00
abstract::Fatty liver has been associated with unfavourable metabolic changes in circulation. To provide insights in fatty liver-related metabolic deviations, we compared metabolic association profile of fatty liver versus metabolic association profiles of genotypes increasing the risk of non-alcoholic fatty liver disease (NAFL...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy124
更新日期:2018-06-15 00:00:00
abstract::Mutations affecting specific splicing regulatory elements offer suitable models to better understand their interplay and to devise therapeutic strategies. Here we characterize a meaningful splicing model in which numerous Hemophilia B-causing mutations, either missense or at the donor splice site (5'ss) of coagulation...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv205
更新日期:2015-09-01 00:00:00
abstract::The gene responsible for cystic fibrosis (CF) contains 27 coding exons and more than 300 independent mutations have been identified. An efficient and optimized strategy is required to identify additional mutations and/or to screen patient samples for the presence of known mutations. We have tested several different co...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.5.801
更新日期:1994-05-01 00:00:00
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::The TRPS1 gene codes for a 1281 amino acids nuclear transcription factor with an unusual combination of different types of zinc finger motifs, including GATA-type DNA-binding and IKAROS-like zinc fingers. TRPS1 is a repressor of GATA-regulated genes and implicated in the human tricho-rhino-phalangeal syndromes. We fou...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg145
更新日期:2003-06-01 00:00:00
abstract::Although genetic variations in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds320
更新日期:2012-11-01 00:00:00
abstract::Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR inter...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu286
更新日期:2014-11-01 00:00:00
abstract::Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is clinically and genetically heterogeneous and can appear as syndromic or non-syndromic. Mucopolysaccharidosis type IIIC (MPS IIIC) is a lethal disorder, caused by mutations in the heparan-alpha-glucosaminide N-acetyltransferase (HGSNA...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv118
更新日期:2015-07-01 00:00:00
abstract::Reduced sarcolemmal integrity in dystrophin-deficient muscles of mdx mice and Duchenne muscular dystrophy (DMD) patients has been reported to result in altered calcium homeostasis. Previous studies have shown a correlative relationship between calcium-dependent protease (calpain) activity in dystrophic muscle and musc...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.21.2645
更新日期:2002-10-01 00:00:00
abstract::Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for >70% of X-linked retinitis pigmentosa (XLRP) and 15-20% of all inherited retinal degeneration. Gene replacement therapy for RPGR-XLRP was hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv134
更新日期:2015-07-15 00:00:00
abstract::Human embryo development occurs through a process that encompasses reprogramming, sequential cleavage divisions and mitotic chromosome segregation and embryonic genome activation. Chromosomal abnormalities may arise during germ cell and/or pre-implantation embryo development, and are a major cause of spontaneous misca...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddn170
更新日期:2008-04-15 00:00:00
abstract::Although considered the most common heritable cause of neurodevelopmental disability, precise prevalence figures for the FMR1 mutation in the general population are lacking. Since no fragile X premutation alleles have yet been observed to originate from FMR1 alleles within the normal size range, there is also little i...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.3.393
更新日期:1994-03-01 00:00:00
abstract::Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy021
更新日期:2018-04-01 00:00:00
abstract::The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expres...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt034
更新日期:2013-05-01 00:00:00
abstract::Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. beta-Cell ATP-sensitive potassium currents can be reconstituted by coexpression of the inward rectifier Kir6.2 and the sulfonylurea receptor (SUR), a member of the ATP-binding casse...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.11.1809
更新日期:1996-11-01 00:00:00
abstract::Aneuploidy is prevalent in human embryos and is the leading cause of pregnancy loss. Many aneuploidies arise during oogenesis, increasing with maternal age. Superimposed on these meiotic aneuploidies are frequent errors occurring during early mitotic divisions, contributing to widespread chromosomal mosaicism. Here we...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy147
更新日期:2018-07-15 00:00:00
abstract::Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to debilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseudarthrosis (nonunion fracture). Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt333
更新日期:2013-12-01 00:00:00
abstract::Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp532
更新日期:2010-02-15 00:00:00
abstract::Nicotine is thought to act on brain monoamine systems that normally mediate diverse motivational behaviors. How monoamine-related genes contribute to behavioral traits (e.g. responses to novel stimuli) comorbid with the susceptibility to nicotine addiction is still poorly understood. We examined the impact of constitu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl206
更新日期:2006-09-15 00:00:00
abstract::Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.10.1771
更新日期:1994-10-01 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