Abstract:
:Single nucleotide polymorphisms (SNPs) that alter exon splicing efficiency are an emerging class of functional genetic variants. Since mutations in low-density lipoprotein receptor (LDLR) are a primary cause of familial hypercholesterolemia, we evaluated whether LDLR SNPs may alter splicing efficiency and cholesterol homeostasis. A SNP within LDLR exon 12, rs688, was identified in silico as neutralizing a putative exon splicing enhancer. Studies in human liver samples established that this SNP was associated with significantly decreased LDLR exon 12 splicing efficiency in women in vivo. In vitro minigene splicing studies qualitatively replicated these in vivo results and demonstrated that rs688 specifically modulates splicing efficiency. These effects on splicing may be physiologically relevant because the presence of the rs688 minor allele associates with increased total and LDL-cholesterol in female members of the Framingham Offspring Study. The largest rs688-associated cholesterol differences were observed in pre-menopausal women. In summary, these studies identify an LDLR SNP present in approximately 60% of Caucasians that is associated with significant 10% increases in total and LDL-cholesterol in pre-menopausal women.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Zhu H,Tucker HM,Grear KE,Simpson JF,Manning AK,Cupples LA,Estus Sdoi
10.1093/hmg/ddm124subject
Has Abstractpub_date
2007-07-15 00:00:00pages
1765-72issue
14eissn
0964-6906issn
1460-2083pii
ddm124journal_volume
16pub_type
杂志文章abstract::Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy014
更新日期:2018-03-15 00:00:00
abstract::Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the human dystrophin gene. About two-thirds of DMD/BMD patients exhibit gross rearrangements in the gene whereas the mutations in the remaining one third are thought to be point mutations or minor structural lesions. By means of various prog...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.11.1877
更新日期:1993-11-01 00:00:00
abstract::Proteins with iron-sulfur (Fe-S) clusters participate in multiple metabolic pathways throughout the cell. The mitochondrial ABC half-transporter Abcb7, which is mutated in X-linked sideroblastic anemia with ataxia in humans, is a functional ortholog of yeast Atm1p and is predicted to export a mitochondrially derived m...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl012
更新日期:2006-03-15 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::Nance-Horan syndrome (NHS) is an X-linked developmental disorder, characterized by bilateral congenital cataracts, dental anomalies, facial dysmorphism and mental retardation. Null mutations in a novel gene, NHS, cause the syndrome. The NHS gene appears to have multiple isoforms as a result of alternative transcriptio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq125
更新日期:2010-06-15 00:00:00
abstract::Several studies have shown that testis-specific gene antigen (TSGA10) could be considered as a cancer testis antigen (CTA), except for one study which has identified it as a tumor suppressor gene. In order to exert its function, TSGA10 interacts closely with hypoxia inducible factor (HIF-1α) and since this interaction...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv461
更新日期:2016-01-15 00:00:00
abstract::The mutation causing myotonic dystrophy (DM) has recently been identified as an unstable CTG trinucleotide repeat located in the 3' untranslated region of a gene encoding for a protein with putative serine-threonine protein kinase activity. In this report we present the genomic sequences of the human and murine DM kin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.3.299
更新日期:1993-03-01 00:00:00
abstract::Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt069
更新日期:2013-06-01 00:00:00
abstract::Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association stu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx375
更新日期:2018-01-01 00:00:00
abstract::Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Different hypotheses exist about the...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy083
更新日期:2018-05-15 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::Monozygotic twin and other epidemiologic studies indicate that epigenetic processes may play an important role in the pathogenesis of inflammatory bowel diseases that commonly affect the colonic mucosa. The peak onset of these disorders in young adulthood suggests that epigenetic changes normally occurring in the colo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq095
更新日期:2010-06-01 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::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::Osteoarthritis (OA) is a common, multifactorial and polygenic skeletal disease that, in its severest form, requires joint replacement surgery to restore mobility and to relieve chronic pain. Using tissues from the articulating joints of 260 patients with OA and a range of in vitro experiments, including CRISPR-Cas9, w...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy257
更新日期:2018-10-01 00:00:00
abstract::Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive study on PDE6C mutation...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq517
更新日期:2011-02-15 00:00:00
abstract::Mutations of the novel renal glomerular genes NPHS1 and NPHS2 encoding nephrin and podocin cause two types of severe nephrotic syndrome presenting in early life, Finnish type congenital nephrotic syndrome (CNF) and a form of autosomal recessive familial focal segmental glomerulosclerosis (SRN1), respectively. To inves...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.4.379
更新日期:2002-02-15 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::The autosomal recessive mouse mutation retinal degeneration 6 (rd6) causes small, white retinal spots and progressive photoreceptor degeneration similar to that observed in human flecked retinal diseases. Using a positional cloning approach, we determined that rd6 mice carry a splice donor mutation in the mouse homolo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.16.1879
更新日期:2002-08-01 00:00:00
abstract::During human spermatogenesis, germ cells undergo dynamic changes in chromatin organization/re-packaging and in transcriptomes. In order to better understand the underlying mechanism(s), scATAC-Seq of 5376 testicular cells from 3 normal men were performed. Data were analyzed in parallel with the scRNA-Seq data of human...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddab006
更新日期:2021-01-12 00:00:00
abstract::We performed a molecular study with 21 microsatellites on a sample of 82 trisomy 13 conceptuses, the largest number of cases studied to date. The parental origin was determined in every case and in 89% the extra chromosome 13 was of maternal origin with an almost equal number of maternal MI and MII errors. The latter ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm148
更新日期:2007-08-15 00:00:00
abstract::In the field of muscular dystrophy, advances in understanding the molecular basis of the various disorders in this group have been rapidly translated into readily applicable diagnostic tests, allowing the provision of more accurate prognostic and genetic counselling. The limb-girdle muscular dystrophies (LGMD) have re...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/8.10.1875
更新日期:1999-01-01 00:00:00
abstract::Autism spectrum disorder (ASD) is characterized by a triad of behavioural impairments including social behaviour. Neuroligin, a trans-synaptic adhesion molecule, has emerged as a penetrant genetic determinant of behavioural traits that signature the neuroatypical behaviours of autism. However, the function of neurolig...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa232
更新日期:2021-01-06 00:00:00
abstract::Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia/myopathy, respectively. The mechanism by which they disrupt mitochondrial cristae, however...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa077
更新日期:2020-06-03 00:00:00
abstract::Mutations in SOX18, VEGFC and Vascular Endothelial Growth Factor 3 underlie the hereditary lymphatic disorders hypotrichosis-lymphedema-telangiectasia (HLT), Milroy-like lymphedema and Milroy disease, respectively. Genes responsible for hereditary lymphedema are key regulators of lymphatic vascular development in the ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt518
更新日期:2014-03-01 00:00:00
abstract::Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by clinical disease caused by weakly virulent mycobacteria, such as environmental mycobacteria and Bacillus Calmette-Guérin vaccines, in otherwise healthy individuals. All known genetic etiologies disrupt interferon (IFN)-γ immunity. Germline bi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy275
更新日期:2018-11-15 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::Gene silencing through aberrant CpG island methylation is a frequent epigenetic defect in hepatocellular carcinoma (HCC). However, nothing is known as yet whether aberrant hypermethylation occurs already in non-neoplastic liver cells from patients with hereditary haemochromatosis who have a clearly elevated risk for d...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm082
更新日期:2007-06-01 00:00:00
abstract::Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which resu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu265
更新日期:2014-10-15 00:00:00
abstract::The molecular genetic events underlying endometrial tumorigenesis are ill-defined at present. We have identified a region on the short arm of chromosome 1 which is frequently deleted in endometrial cancers. The region of deletion has been localized to bands 1p32-33. Deletion of 1p32-33 is seen more frequently in cance...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.7.1017
更新日期:1996-07-01 00:00:00