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 mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional characterization of six missense mutations applying the baculovirus system to express recombinant mutant and wildtype chimeric PDE6C/PDE5 proteins in Sf9 insect cells. Purified proteins were analyzed using Western blotting, phosphodiesterase (PDE) activity measurements as well as inhibition assays by zaprinast and Pγ. Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles. For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively. We also observed differences for Pγ inhibition. The p.E790K mutant, with an IC₅₀ value of 2.7 nm is 20.7-fold more sensitive for Pγ inhibition, whereas the p.Y323N mutant with an IC₅₀ of 158 nm is 3-fold less sensitive when compared with the wildtype control.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Grau T,Artemyev NO,Rosenberg T,Dollfus H,Haugen OH,Cumhur Sener E,Jurklies B,Andreasson S,Kernstock C,Larsen M,Zrenner E,Wissinger B,Kohl Sdoi
10.1093/hmg/ddq517subject
Has Abstractpub_date
2011-02-15 00:00:00pages
719-30issue
4eissn
0964-6906issn
1460-2083pii
ddq517journal_volume
20pub_type
杂志文章abstract::Following a screen for neuromuscular mouse mutants, we identified ostes, a novel N-ethyl N-nitrosourea-induced mouse mutant with muscle atrophy. Genetic and biochemical evidence shows that upregulation of the novel, uncharacterized transient receptor potential polycystic (TRPP) channel PKD1L2 (polycystic kidney diseas...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp304
更新日期:2009-10-01 00:00:00
abstract::Osteoarthritis is a common, complex disease with no curative therapy. In this review, we summarize current knowledge on disease aetiopathogenesis and outline genetics and genomics approaches that are helping catalyse a much-needed improved understanding of the biological underpinning of disease development and progres...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddx302
更新日期:2017-10-01 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::Mutations in the ORF15 exon of the RPGR gene cause a common form of X-linked retinitis pigmentosa, which often results in severe loss of vision. In dogs and mice, gene augmentation therapy has been shown to arrest the progressive degeneration of rod and cone photoreceptors. However, the distribution of potentially tre...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw361
更新日期:2016-12-15 00:00:00
abstract::Cone photoreceptors (cones) are essential for high-resolution daylight vision and colour perception. Loss of cones in hereditary retinal diseases has a dramatic impact on human vision. The mechanisms underlying cone death are poorly understood, and consequently, there are no treatments available. Previous studies sugg...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw219
更新日期:2016-09-01 00:00:00
abstract::Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl222
更新日期:2006-09-15 00:00:00
abstract::Lethal white foal syndrome (LWFS) is a congenital anomaly of horses characterized by a white coat colour and aganglionosis of the bowel, which is similar to Hirschsprung disease (HSCR). We decided to investigate possible mutations of the endothelin-B receptor gene ( EDNRB ) in LWFS as recent studies in mutant rodents ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.6.1047
更新日期:1998-06-01 00:00:00
abstract::Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other lo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx430
更新日期:2018-02-15 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::Mitochondria contain a dedicated translation system, which is responsible for the intramitochondrial synthesis of 13 mitochondrial DNA (mtDNA)-encoded polypeptides essential for the biogenesis of oxidative phosphorylation (OXPHOS) complexes I and III-V. Mutations in nuclear genes encoding factors involved in mitochond...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy441
更新日期:2019-05-01 00:00:00
abstract::As the powerhouses of the eukaryotic cell, mitochondria must maintain their genomes which encode proteins essential for energy production. Mitochondria are characterized by guanine-rich DNA sequences that spontaneously form unusual three-dimensional structures known as G-quadruplexes (G4). G4 structures can be problem...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa043
更新日期:2020-05-28 00:00:00
abstract::X-linked Kallmann's syndrome (KS) is a genetic disease characterized by anosmia and hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GnRH)-producing neurons. Deletions or point mutations of a gene located at Xp22.3 (KAL1) are responsible for t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh309
更新日期:2004-11-15 00:00:00
abstract::Familial infantile myasthenia is an autosomal recessive disorder, recently classified as congenital myasthenic syndrome type Ia. Onset of symptoms is at birth to early childhood with significant myasthenic weakness and possible respiratory distress, followed later in life by symptoms of mild to moderate myasthenia. Th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.4.635
更新日期:1997-04-01 00:00:00
abstract:BACKGROUND:Single variant approaches have been successful in identifying DNA methylation quantitative trait loci (mQTL), although as with complex traits they lack the statistical power to identify the effects from rare genetic variants. We have undertaken extensive analyses to identify regions of low frequency and rare...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw283
更新日期:2016-10-01 00:00:00
abstract::The clinical manifestations of inherited neurodegenerative diseases are often delayed for periods from years to decades. This observation has led to the idea that, in these disorders, neurons die from cumulative damage. A critical prediction of the cumulative damage hypothesis is that the probability of neuronal death...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/10.20.2269
更新日期:2001-10-01 00:00:00
abstract::Circletail is one of only two mouse mutants that exhibit the most severe form of neural tube defect (NTD), termed craniorachischisis. In this disorder, almost the entire brain and spinal cord is affected, owing to a failure to initiate neural tube closure. Craniorachischisis is a significant cause of lethality in huma...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg014
更新日期:2003-01-15 00:00:00
abstract::Mitochondrial dysfunction plays an important role in the etiology of neurodegenerative diseases. However, the progressive nature of neuronal loss in genetic models of mitochondrial dysfunction suggests the presence of compensatory mechanisms promoting neuronal survival under these conditions. Here, we identified the e...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds500
更新日期:2013-03-01 00:00:00
abstract::Atopic (allergic) asthma is the most common disease of childhood and is strongly genetic in origin. Many genome-wide screens for asthma and its associated traits have now been carried out, and genetic linkage has been consistently identified in several regions. It is probable that these loci contain major genes influe...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/9.16.2359
更新日期:2000-10-01 00:00:00
abstract::Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise a...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddv475
更新日期:2016-04-15 00:00:00
abstract::The members of the huntingtin-interacting protein-1 (HIP1) family, HIP1 and HIP1-related (HIP1r), are multi-domain proteins that interact with inositol lipids, clathrin and actin. HIP1 is over-expressed in a variety of cancers and both HIP1 and HIP1r prolong the half-life of multiple growth factor receptors. To better...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm076
更新日期:2007-06-01 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::Schizophrenia may arise from subtle abnormalities in brain development due to alterations in the functions of candidate susceptibility genes such as Disrupted-in-schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1). To provide novel insights into the functions of DISC1 in brain development, we mapped the expression of zebr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn361
更新日期:2009-02-01 00:00:00
abstract::Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp135
更新日期:2009-06-15 00:00:00
abstract::Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unk...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx337
更新日期:2017-11-15 00:00:00
abstract::The infantile neuronal ceroid lipofuscinosis (INCL), a rare (one in 100 000 births) but one of the most lethal inherited neurodegenerative storage disorders of childhood, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in s-acylated (palmitoylate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl078
更新日期:2006-05-15 00:00:00
abstract::Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora)...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr108
更新日期:2011-06-01 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::Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite for population-based disease gene mapping. Variable patterns across the human genome are now recognized, both between regions and populations. Here, we demonstrate that LD may also vary within a genomic region in a haplotype-specific manne...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:
更新日期:2003-03-15 00:00:00
abstract::Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results f...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm054
更新日期:2007-05-15 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