Abstract:
:Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/- and Tsc2+/- mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary to prevent tumour formation. Patients with TSC often develop renal cysts and those with inherited co-deletions of the autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) develop severe, early onset, polycystic kidneys. Using mouse models, we showed a genetic interaction between Tsc1 and Tsc2 with Pkd1 and confirmed an mTOR-independent pathway of renal cystogenesis. We observed that the Tsc and Pkd1 gene products helped regulate primary cilia length and, consistent with the function of this organelle in modulating cell polarity, found that many dividing pre-cystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2 and Pkd1 heterozygous mice were highly misoriented. We therefore propose that defects in cell polarity underlie TSC and ADPKD-associated cystic disease and targeting of this pathway may be of key therapeutic benefit.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Bonnet CS,Aldred M,von Ruhland C,Harris R,Sandford R,Cheadle JPdoi
10.1093/hmg/ddp149subject
Has Abstractpub_date
2009-06-15 00:00:00pages
2166-76issue
12eissn
0964-6906issn
1460-2083pii
ddp149journal_volume
18pub_type
杂志文章abstract::Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding v...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt365
更新日期:2013-12-20 00:00:00
abstract::Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized by a combination of pigmentary and auditory abnormalities. Approximately 20% of WS2 cases are associated with mutations in the gene encoding microphthalmia-associated transcription factor (MITF). MITF plays a critical role in the develop...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.8.1431
更新日期:1999-08-01 00:00:00
abstract::Mutations in the survival motor neuron (SMN1) gene lead to the neuromuscular disease spinal muscular atrophy (SMA). Although SMA is primarily considered as a motor neuron disease, the importance of muscle defects in its pathogenesis has not been fully examined. We use both primary cell culture and two different SMA mo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu142
更新日期:2014-08-15 00:00:00
abstract::There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established typ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.20.2967
更新日期:2000-12-12 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz044
更新日期:2019-07-01 00:00:00
abstract::The transcription factor SOX10 is mutated in the human neurocristopathy Waardenburg-Shah syndrome (WS4), which is characterized by enteric aganglionosis and pigmentation defects. SOX10 directly regulates genes expressed in neural crest lineages, including the enteric ganglia and melanocytes. Although some SOX10 target...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi442
更新日期:2006-01-15 00:00:00
abstract::While constructing a cDNA library of human embryos, we have isolated a clone homologous to jumonji, a mouse gene required for neural tube formation. We have determined the complete coding sequence of the human homologue (JMJ) and deduced the amino acid sequence of the putative protein. We show here that human and mous...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.10.1637
更新日期:1996-10-01 00:00:00
abstract::Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMA and SCA1) were surveyed in phenotypically normal individuals from three continental populations. This is the first analysis to examine the population dynamics of these five disease-related trinucleotide repeats in the same individuals from worldwide popul...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.9.1485
更新日期:1995-09-01 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::Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+ binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx056
更新日期:2017-04-01 00:00:00
abstract::A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11. Over one hundred such deletions have now been examined and a minimally deleted region of 300kb defined. Within these sequences we have identified a gene expressed during human and murine ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.12.2099
更新日期:1993-12-01 00:00:00
abstract::The Pearson marrow-pancreas syndrome (MIM 557000) is a disorder involving the hematopoietic system and the exocrine pancreas in early infancy. We have previously shown that this disease results from a defect of oxidative phosphorylation associated with deletions of the mitochondrial DNA. We present here a series of 21...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.8.1327
更新日期:1995-08-01 00:00:00
abstract::Directed hepatocyte differentiation from human induced pluripotent stem cells (iPSCs) potentially provides a unique platform for modeling liver genetic diseases and performing drug-toxicity screening in vitro. Wilson's disease is a genetic disease caused by mutations in the ATP7B gene, whose product is a liver transpo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr223
更新日期:2011-08-15 00:00:00
abstract::Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz110
更新日期:2019-09-15 00:00:00
abstract::The term 'dynamic mutation' was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of mutation. The past decade has seen dynamic mutations uncovered as the molecular basis for a growing number of human genetic diseases and for all of the characterized 'rare' ch...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/10.20.2187
更新日期:2001-10-01 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::Bardet-Biedl syndrome is an autosomal recessive disorder characterized by mental retardation, obesity, retinitis pigmentosa, polydactyly and hypogonadism. Individuals with this disorder also have an increased incidence of hypertension, diabetes mellitus, and renal and cardiac anomalies. We previously identified a locu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.8.1331
更新日期:1994-08-01 00:00:00
abstract::The polymorphic K variant of the butyrylcholinesterase ( BCHE-K ) gene recently has been demonstrated to have an elevated frequency in Alzheimer's disease (AD) patients carrying the epsilon4 allele of the apolipoprotein (APO E) gene when compared with a control population. We therefore genotyped a large series of path...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.5.937
更新日期:1998-05-01 00:00:00
abstract::Research of cilia has gained significant momentum in the last 15 years, as an increasing number of human genetic diseases were found to be caused by disruption of a protein that localizes to cilia. These ciliopathies are as diverse as the functions of the associated proteins, covering a spectrum of overlapping phenoty...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddr354
更新日期:2011-10-15 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are the two common neurodegenerative diseases that have been associated with the GGGGCC·GGCCCC repeat RNA expansion in a noncoding region of C9orf72. It has been previously reported that unconventional repeat-associated non-ATG (RAN) translation of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv005
更新日期:2015-05-01 00:00:00
abstract::Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda S = 2.4). It is recognized that the MHC contains multiple susceptibility loci (refe...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/5.supplement_1.1443
更新日期:1996-01-01 00:00:00
abstract::Biallelic loss-of-function mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), an autosomal recessive condition mainly characterized by craniofacial and limb malformations. However, the pathogenic cellular mechanisms responsible for this syndrome are entirely unknown. Here, we use...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx078
更新日期:2017-06-15 00:00:00
abstract::Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu406
更新日期:2014-12-20 00:00:00
abstract::A vast portion of intellectual disability and autism spectrum disorders is genetically caused by mutations in chromatin modulators. These proteins play key roles in development and are also highly expressed in the adult brain. Specifically, the pivotal role of chromatin regulation in transcription has placed enhancers...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddz196
更新日期:2019-11-21 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::Differential allelic expression has been shown to be common in mice, humans and maize, and variability in the expression of polymorphic alleles has been associated with human disease. Here, we describe the differential expression pattern of Paraoxonase-1, a gene involved in lipid metabolism and implicated in the forma...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn222
更新日期:2008-11-01 00:00:00
abstract::SPEG, a member of the myosin light chain kinase family, is localized at the level of triad surrounding myofibrils in skeletal muscles. In humans, SPEG mutations are associated with centronuclear myopathy and cardiomyopathy. Using a striated muscle specific Speg-knockout (KO) mouse model, we have previously shown that ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa276
更新日期:2020-12-23 00:00:00
abstract::Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine stretch in the MJD gene-encoded protein, ataxin-3. Using a series of deletion constructs expressing ataxin-3 fragments with expanded polyglutamine stretches, we observed aggregate formation and cell dea...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.1.69
更新日期:2000-01-01 00:00:00
abstract::Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar...
journal_title:Human molecular genetics
pub_type: 杂志文章,meta分析
doi:10.1093/hmg/ddt575
更新日期:2014-04-01 00:00:00
abstract::Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Prev...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds061
更新日期:2012-06-01 00:00:00