Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1.

Abstract:

:Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-β (TGF-β) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-β family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-β1 signaling triggered by proTGF-β1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum (ER), and cleaved proTGF-β1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-β1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-β1, specifically, the intracellular cleavage of proTGF-β1 in the ER.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Shiga A,Nozaki H,Yokoseki A,Nihonmatsu M,Kawata H,Kato T,Koyama A,Arima K,Ikeda M,Katada S,Toyoshima Y,Takahashi H,Tanaka A,Nakano I,Ikeuchi T,Nishizawa M,Onodera O

doi

10.1093/hmg/ddr063

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

1800-10

issue

9

eissn

0964-6906

issn

1460-2083

pii

ddr063

journal_volume

20

pub_type

杂志文章
  • Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly.

    abstract::An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddw431

    authors: Friederich MW,Erdogan AJ,Coughlin CR 2nd,Elos MT,Jiang H,O'Rourke CP,Lovell MA,Wartchow E,Gowan K,Chatfield KC,Chick WS,Spector EB,Van Hove JLK,Riemer J

    更新日期:2017-02-15 00:00:00

  • Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.

    abstract::Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the spectrum of sequence variants in the haemochromatosis ( HFE ) gene. This population screening approach, utilizing a combined heteroduplex and single-strand conformation po...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/8.8.1517

    authors: de Villiers JN,Hillermann R,Loubser L,Kotze MJ

    更新日期:1999-08-01 00:00:00

  • Zn²⁺ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation.

    abstract::Mutations in ATP13A2 (PARK9) cause Kufor-Rakeb syndrome (KRS) characterized by juvenile-onset parkinsonism, pyramidal signs and dementia. PARK9 belongs to type 5 P-type ATPase with its putative function as a cation transporter. Loss of PARK9 leads to lysosomal dysfunction and subsequent α-synuclein (α-Syn) accumulatio...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddt572

    authors: Tsunemi T,Krainc D

    更新日期:2014-06-01 00:00:00

  • Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families.

    abstract::Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddg270

    authors: Pankratz N,Nichols WC,Uniacke SK,Halter C,Murrell J,Rudolph A,Shults CW,Conneally PM,Foroud T,Parkinson Study Group.

    更新日期:2003-10-15 00:00:00

  • Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice.

    abstract::Peroxisome proliferator-activated receptors (PPARs) are ligand-mediated transcription factors, which control both lipid and energy metabolism and inflammation pathways. PPARγ agonists are effective in the treatment of metabolic diseases and, more recently, neurodegenerative diseases, in which they show promising neuro...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/dds355

    authors: Dumont M,Stack C,Elipenahli C,Jainuddin S,Gerges M,Starkova N,Calingasan NY,Yang L,Tampellini D,Starkov AA,Chan RB,Di Paolo G,Pujol A,Beal MF

    更新日期:2012-12-01 00:00:00

  • Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study.

    abstract::A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddn132

    authors: Assimes TL,Knowles JW,Basu A,Iribarren C,Southwick A,Tang H,Absher D,Li J,Fair JM,Rubin GD,Sidney S,Fortmann SP,Go AS,Hlatky MA,Myers RM,Risch N,Quertermous T

    更新日期:2008-08-01 00:00:00

  • Common haplotypes in five genes influence genetic variance of LDL and HDL cholesterol in the general population.

    abstract::We studied the association between common haplotypes in six relevant lipid metabolism genes with plasma lipid levels. We selected single-nucleotide polymorphisms (SNPs) in the cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic triglyceride lipase (HL), low-density lipoprotein cholesterol rece...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/11.12.1477

    authors: Knoblauch H,Bauerfeind A,Krähenbühl C,Daury A,Rohde K,Bejanin S,Essioux L,Schuster H,Luft FC,Reich JG

    更新日期:2002-06-01 00:00:00

  • Evolution of the sperm methylome of primates is associated with retrotransposon insertions and genome instability.

    abstract::Changes in gene expression resulting from epigenetic and/or genetic changes play an important role in the evolutionary divergence of phenotypes. To explore how epigenetic and genetic changes are linked during primate evolution, we have compared the genome-wide DNA methylation profiles (methylomes) of humans and chimpa...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddx236

    authors: Fukuda K,Inoguchi Y,Ichiyanagi K,Ichiyanagi T,Go Y,Nagano M,Yanagawa Y,Takaesu N,Ohkawa Y,Imai H,Sasaki H

    更新日期:2017-09-15 00:00:00

  • A mutational hot spot in keratin 10 (KRT 10) in patients with epidermolytic hyperkeratosis.

    abstract::Epidermolytic hyperkeratosis (EHK), (bullous congenital ichthyosiform erythroderma), is an autosomal dominant human skin disorder. Recently, we and others have described mutations in keratins 1 and 10 (K1 and K10) in patients with this disease. Structure-function models predict that these mutations would impair normal...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/2.12.2147

    authors: Rothnagel JA,Fisher MP,Axtell SM,Pittelkow MR,Anton-Lamprecht I,Huber M,Hohl D,Roop DR

    更新日期:1993-12-01 00:00:00

  • Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells.

    abstract::Cystathionine beta-synthase (CBS) deficiency is the major cause of homocystinuria in humans. The most frequent symptoms of homocystinuria include: dislocated optic lenses, vascular disorders, skeletal abnormalities and mental retardation. Patients with this deficiency have elevated levels of homocyst(e)ine, methionine...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/2.10.1633

    authors: Kraus JP,Le K,Swaroop M,Ohura T,Tahara T,Rosenberg LE,Roper MD,Kozich V

    更新日期:1993-10-01 00:00:00

  • EIF4A3 deficient human iPSCs and mouse models demonstrate neural crest defects that underlie Richieri-Costa-Pereira syndrome.

    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

    authors: Miller EE,Kobayashi GS,Musso CM,Allen M,Ishiy FAA,de Caires LC Jr,Goulart E,Griesi-Oliveira K,Zechi-Ceide RM,Richieri-Costa A,Bertola DR,Passos-Bueno MR,Silver DL

    更新日期:2017-06-15 00:00:00

  • Epigenetic defects of hepatocellular carcinoma are already found in non-neoplastic liver cells from patients with hereditary haemochromatosis.

    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

    authors: Lehmann U,Wingen LU,Brakensiek K,Wedemeyer H,Becker T,Heim A,Metzig K,Hasemeier B,Kreipe H,Flemming P

    更新日期:2007-06-01 00:00:00

  • Non-disjunction of chromosome 13.

    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

    authors: Bugge M,Collins A,Hertz JM,Eiberg H,Lundsteen C,Brandt CA,Bak M,Hansen C,Delozier CD,Lespinasse J,Tranebjaerg L,Hahnemann JM,Rasmussen K,Bruun-Petersen G,Duprez L,Tommerup N,Petersen MB

    更新日期:2007-08-15 00:00:00

  • Rapid identification of gene sequences for transcriptional map assembly by direct cDNA screening of genomic reference libraries.

    abstract::We have used the direct cDNA screening protocol to identify sequences transcribed in cerebral cortex from a reference library of human Xq28. To derive coding sequences from these genomic clones, we first identified fragments containing transcribed sequences and subjected these to exon trapping or to partial sequencing...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/3.11.2019

    authors: Lawrence BJ,Schwabe W,Kioschis P,Coy JF,Poustka A,Brennan MB,Hochgeschwender U

    更新日期:1994-11-01 00:00:00

  • Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression.

    abstract::Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been studied both by DNA sequencing and by emerin protein expression. Fourteen had mutations in the X-linked emerin gene, while three showed evidence of autosomal inheritance. Twelve of the 14 emerin mutations caused early termination of translation...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/7.5.855

    authors: Manilal S,Recan D,Sewry CA,Hoeltzenbein M,Llense S,Leturcq F,Deburgrave N,Barbot J,Man N,Muntoni F,Wehnert M,Kaplan J,Morris GE

    更新日期:1998-05-01 00:00:00

  • Population genetics of trinucleotide repeat polymorphisms.

    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

    authors: Watkins WS,Bamshad M,Jorde LB

    更新日期:1995-09-01 00:00:00

  • A novel mouse model that recapitulates adult-onset glycogenosis type 4.

    abstract::Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme (GBE). The diagnostic hallmark of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variab...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddv385

    authors: Orhan Akman H,Emmanuele V,Kurt YG,Kurt B,Sheiko T,DiMauro S,Craigen WJ

    更新日期:2015-12-01 00:00:00

  • Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation.

    abstract::The widespread use of persistent organic polybrominated diphenyl ethers (PBDEs) as commercial flame retardants has raised concern about potential long-lived effects on human health. Epigenetic mechanisms, such as DNA methylation, are responsive to environmental influences and have long-lasting consequences. Autism spe...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/dds046

    authors: Woods R,Vallero RO,Golub MS,Suarez JK,Ta TA,Yasui DH,Chi LH,Kostyniak PJ,Pessah IN,Berman RF,LaSalle JM

    更新日期:2012-06-01 00:00:00

  • Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.

    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

    authors: Koziell A,Grech V,Hussain S,Lee G,Lenkkeri U,Tryggvason K,Scambler P

    更新日期:2002-02-15 00:00:00

  • Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy.

    abstract::X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) an...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddr536

    authors: Schlüter A,Espinosa L,Fourcade S,Galino J,López E,Ilieva E,Morató L,Asheuer M,Cook T,McLaren A,Reid J,Kelly F,Bates S,Aubourg P,Galea E,Pujol A

    更新日期:2012-03-01 00:00:00

  • An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome.

    abstract::ICF syndrome has been described as the association of variable immunodeficiency, facial anomalies and centromeric heterochromatin instability. Since the chromosome rearrangements seen in cells of ICF patients are reminiscent of the chromosomal changes induced by the undermethylating agent 5-azacytidine in the late S-p...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/2.6.731

    authors: Jeanpierre M,Turleau C,Aurias A,Prieur M,Ledeist F,Fischer A,Viegas-Pequignot E

    更新日期:1993-06-01 00:00:00

  • Cloning of the Huntington disease region in yeast artificial chromosomes.

    abstract::The gene responsible for Huntington disease has been localized to a 2.5 million base pair (Mb) region between the loci D4S10 and D4S168 on the short arm of chromosome 4. As part of a strategy to clone the HD gene on the basis of its chromosomal location, we isolated genomic DNA from the HD region as a set of overlappi...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/1.3.149

    authors: Zuo J,Robbins C,Taillon-Miller P,Cox DR,Myers RM

    更新日期:1992-06-01 00:00:00

  • Identification of consensus motifs associated with mitotic recombination and clinical characteristics in patients with paternal uniparental isodisomy of chromosome 11.

    abstract::Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddw023

    authors: Ohtsuka Y,Higashimoto K,Oka T,Yatsuki H,Jozaki K,Maeda T,Kawahara K,Hamasaki Y,Matsuo M,Nishioka K,Joh K,Mukai T,Soejima H

    更新日期:2016-04-01 00:00:00

  • Partial characterisation of murine huntingtin and apparent variations in the subcellular localisation of huntingtin in human, mouse and rat brain.

    abstract::Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of a CAG repeat in a gene coding for a protein of unknown function. We have raised a polyclonal antibody against a 12 amino acid peptide (residues 2110-2121 of human huntingtin) which specifically recognises huntingtin on West...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/5.4.481

    authors: Wood JD,MacMillan JC,Harper PS,Lowenstein PR,Jones AL

    更新日期:1996-04-01 00:00:00

  • Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.

    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

    authors: Sun Y,Witte DP,Ran H,Zamzow M,Barnes S,Cheng H,Han X,Williams MT,Skelton MR,Vorhees CV,Grabowski GA

    更新日期:2008-08-01 00:00:00

  • Downstream targets of GWAS-detected genes for breast, lung, and prostate and colon cancer converge to G1/S transition pathway.

    abstract::Genome-wide association studies (GWASs) identified over 500 single nucleotide polymorphisms (SNPs) influencing cancer risk. It is logical to expect the cancer-associated genes to cluster in pathways directly involved in carcinogenesis, e.g. cell cycle. Nevertheless, analyses of the GWAS-detected cancer risk genes usua...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddx050

    authors: Gorlova OY,Demidenko EI,Amos CI,Gorlov IP

    更新日期:2017-04-15 00:00:00

  • Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein.

    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

    authors: Taylor JP,Tanaka F,Robitschek J,Sandoval CM,Taye A,Markovic-Plese S,Fischbeck KH

    更新日期:2003-04-01 00:00:00

  • Cellular consequences of oxidative stress in riboflavin responsive multiple acyl-CoA dehydrogenation deficiency patient fibroblasts.

    abstract::Mitochondrial dysfunction and oxidative stress are central to the molecular pathology of many human diseases. Riboflavin responsive multiple acyl-CoA dehydrogenation deficiency (RR-MADD) is in most cases caused by variations in the gene coding for electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Curr...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu146

    authors: Cornelius N,Corydon TJ,Gregersen N,Olsen RK

    更新日期:2014-08-15 00:00:00

  • The establishment of telomerase-immortalized cell lines representing human chromosome instability syndromes.

    abstract::The limited life span of normal human cells represents a substantial obstacle for biochemical analysis, genetic manipulation and genetic screens. To overcome this technical barrier, immortal human cell lines are often derived from tumors or produced by transformation with viral oncogenes such as SV40 large T antigen. ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/9.3.403

    authors: Ouellette MM,McDaniel LD,Wright WE,Shay JW,Schultz RA

    更新日期:2000-02-12 00:00:00

  • Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility.

    abstract::Three distinct regions, designated AZFa, b and c from proximal to distal Yq, are required for normal spermato-genesis in humans. Deletions involving AZFa (deletion interval 5C/D) seem to occur less frequently in infertile men and to be associated with a more severe testicular phenotype, with almost complete absence of...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/9.8.1161

    authors: Foresta C,Ferlin A,Moro E

    更新日期:2000-05-01 00:00:00