Abstract:
:Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
De Jonghe C,Esselens C,Kumar-Singh S,Craessaerts K,Serneels S,Checler F,Annaert W,Van Broeckhoven C,De Strooper Bdoi
10.1093/hmg/10.16.1665subject
Has Abstractpub_date
2001-08-01 00:00:00pages
1665-71issue
16eissn
0964-6906issn
1460-2083journal_volume
10pub_type
杂志文章abstract::The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that te...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn419
更新日期:2009-03-01 00:00:00
abstract::The FKHR gene, which contains a forkhead DNA-binding motif, is fused to either PAX3 or PAX7 by the t(2;13) or t(1;13) translocation in alveolar rhabdomyosarcoma,respectively. These tumors express chimeric transcripts encoding the N-terminal portion of either PAX protein fused to the C-terminal portion of FKHR. To unde...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.12.2355
更新日期:1995-12-01 00:00:00
abstract::A proportion of human breast cancers result from an inherited predisposition to the disease. Mutations in the BRCA2 gene confer a high risk of breast cancer and are responsible for almost half of these cases. The recent cloning of the human BRCA2 gene has revealed that it encodes a large protein having little signific...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.2.291
更新日期:1997-02-01 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::The RIG-I-like receptors (RLRs)--RIG-I, IFIH1 (or MDA5) and LGP2--are thought to be key actors in the innate immune system, as they play a major role in sensing RNA viruses in the cytosol of host cells. Despite the increasingly recognized importance of the RLR family in antiviral immunity, no population genetic studie...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr377
更新日期:2011-11-15 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::Southern blot analysis of the COL4A5 gene in a 6 year old Italian Alport patient (proband VIZ) showed the loss of an MspI site that was present in the mother and control DNAs. PCR amplification and DNA sequencing revealed a single G-->A nucleotide change. The mutation results in substitution of a glutamic acid for a g...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/1.2.127
更新日期:1992-05-01 00:00:00
abstract::We describe and functionally characterize six mutations of the acetylcholine receptor (AChR) epsilon subunit gene in three congenital myasthenic syndrome patients. Endplate studies demonstrated severe endplate AChR deficiency, dispersed endplate regions and well preserved junctional folds in all three patients. Electr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.5.753
更新日期:1997-05-01 00:00:00
abstract::Plasmid pRSVL persisted and expressed luciferase for at least 19 months in mouse skeletal muscle after intramuscular injection. Other injected plasmids also stably expressed long-term suggesting that any plasmid DNA could stably persist and express in muscle. Plasmid DNA was demonstrated by quantitative PCR in some of...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/1.6.363
更新日期:1992-09-01 00:00:00
abstract::We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rear...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.4.615
更新日期:1995-04-01 00:00:00
abstract::Family history of endometrial cancer increases the risk of developing the disease, but it is still largely unknown which germ-line genetic factors are involved in the aetiology of endometrial cancer. In a Swedish population-based case-control study including 705 cases and 1565 controls, we examined common variation in...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl451
更新日期:2007-01-15 00:00:00
abstract::The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chro...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr074
更新日期:2011-05-15 00:00:00
abstract::Genetic and environmental influences are thought to interact in their contribution to the etiology of major neuropsychiatric disorders. One of the best replicated findings obtained in genome-wide association studies are genetic variants in the CACNA1C gene. Here, we used our constitutive heterozygous Cacna1c rat model...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz235
更新日期:2019-12-15 00:00:00
abstract::Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn135
更新日期:2008-08-01 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::One mechanism by which endogenous microRNAs (miRNAs) function is to suppress translation of target mRNAs. Computational identification of target mRNAs is hampered by the partial complementarity between miRNAs and their targets and the lack of in vivo approaches to identify targets. Here, we identify mRNAs that are reg...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi397
更新日期:2005-12-15 00:00:00
abstract::The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv514
更新日期:2016-02-15 00:00:00
abstract::CREB-binding protein (CBP, CREBBP, KAT3A) and its closely related paralogue p300 (EP300, KAT3B), together termed p300/CBP, are histone/lysine acetyl-transferases that control gene expression by modifying chromatin-associated proteins. Here, we report roles for both of these chromatin-modifying enzymes in mouse sex det...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx398
更新日期:2018-01-01 00:00:00
abstract::Albinism is a group of genetic disorders characterized by deficient synthesis of melanin pigment. In oculocutaneous albinism (OCA) the pigment deficiency involves the skin, hair, and eyes, whereas in ocular albinism (OA) the defect involves principally the visual system. Type I (tyrosinase-deficient) OCA results from ...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/3.suppl_1.1469
更新日期:1994-01-01 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::Filamin B (FLNB) is a cytoplasmic protein that regulates the cytoskeletal network by cross-linking actin, linking cell membrane to the cytoskeleton and regulating intracellular signaling pathways responsible for skeletal development (Stossel, T.P., Condeelis, J., Cooley, L., Hartwig, J.H., Noegel, A., Schleicher, M. a...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm114
更新日期:2007-07-15 00:00:00
abstract::Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy358
更新日期:2019-02-15 00:00:00
abstract::Cytochrome c oxidase (COX) defects are found in a clinically and genetically heterogeneous group of mitochondrial disorders. To date, mutations in only two nuclear genes causing COX deficiency have been described. We report here a genetic linkage study of a consanguineous family with an isolated COX defect and subsequ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.8.1245
更新日期:2000-05-01 00:00:00
abstract::Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu317
更新日期:2014-11-15 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::The breast cancer susceptibility gene BRCA2 encodes a protein of 3418 amino acids which does not exhibit substantial sequence similarity to any other protein in the public databases. A dot matrix comparison of BRCA2 with itself revealed an eight times repeated motif in the segment of the protein encoded by exon 11. As...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.1.53
更新日期:1997-01-01 00:00:00
abstract::Over the past decades the search for disease causing variants has been focusing exclusively on the coding genome. This highly selective approach has been extremely successful resulting in the identification of thousands of disease genes, but ignores the functional and therefore disease relevance of the rest of the gen...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw205
更新日期:2016-10-01 00:00:00
abstract::Neurofibromatosis type 1 (NF1) is a common inherited cancer predisposition syndrome. The NF1 gene product, neurofibromin, is hypothesized to function as a tumor suppressor and nearly all NF1 patients develop benign peripheral nerve tumors. These neurofibromas presumably arise from NF1 inactivation in S100(+)Schwann ce...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.7.1059
更新日期:2000-04-12 00:00:00
abstract::The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeos...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv226
更新日期:2015-09-15 00:00:00
abstract::Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting > 25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spa...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi187
更新日期:2005-07-01 00:00:00