Abstract:
:Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10-30 for rs4253311 and 1.85 × 10-19 for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Benyamin B,Maihofer AX,Schork AJ,Hamilton BA,Rao F,Schmid-Schönbein GW,Zhang K,Mahata M,Stridsberg M,Schork NJ,Biswas N,Hook VY,Wei Z,Montgomery GW,Martin NG,Nievergelt CM,Whitfield JB,O'Connor DTdoi
10.1093/hmg/ddw380subject
Has Abstractpub_date
2017-01-01 00:00:00pages
233-242issue
1eissn
0964-6906issn
1460-2083pii
ddw380journal_volume
26pub_type
杂志文章abstract::A long-term goal of modeling Huntington's disease (HD) is to recapitulate the cardinal features of the disease in mice that express both mutant and wild-type (WT) huntingtin (Htt), as HD commonly manifests as a heterozygous condition in humans, and loss of WT Htt is associated with loss-of-function. In a new heterozyg...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu166
更新日期:2014-09-01 00:00:00
abstract::Epidermolytic hyperkeratosis (EHK) is a blistering skin disease inherited as an autosomal-dominant trait. The disease is caused by genetic defects of the epidermal keratin K1 or K10, leading to an impaired tonofilament network of differentiating epidermal cells. Here, we describe for the first time a kindred with rece...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl028
更新日期:2006-04-01 00:00:00
abstract::Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration r...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy003
更新日期:2018-03-01 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::Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi380
更新日期:2005-11-15 00:00:00
abstract::Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinica...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy182
更新日期:2018-08-01 00:00:00
abstract::Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and l...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr385
更新日期:2011-12-01 00:00:00
abstract::The high affinity receptor for IgE (Fc epsilon RI) has a central role in mast cell degranulation and IgE mediated allergy. A systematic search through the coding regions of the beta subunit of Fc epsilon RI (Fc epsilon RI-beta) has identified a novel coding polymorphism in exon seven. An adenine to guanine substitutio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.7.959
更新日期:1996-07-01 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::Selenoprotein N (SelN) deficiency causes a group of inherited neuromuscular disorders termed SEPN1-related myopathies (SEPN1-RM). Although the function of SelN remains unknown, recent data demonstrated that it is dispensable for mouse embryogenesis and suggested its involvement in the regulation of ryanodine receptors...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq515
更新日期:2011-02-15 00:00:00
abstract::The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expres...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt034
更新日期:2013-05-01 00:00:00
abstract::Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA prop...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq196
更新日期:2010-07-15 00:00:00
abstract::Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains u...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds038
更新日期:2012-05-15 00:00:00
abstract::Mutations in Alsin are associated with chronic juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. The primary pathology and pathogenic mechanism of the disease remain largely unknown. Here we show that alsin-deficient mice have motor impai...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm251
更新日期:2007-12-01 00:00:00
abstract::Proper localization and anchorage of nuclei within skeletal muscle is critical for cellular function. Alterations in nuclear anchoring proteins modify a number of cellular functions including mechanotransduction, nuclear localization, chromatin positioning/compaction and overall organ function. In skeletal muscle, nes...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu310
更新日期:2014-11-15 00:00:00
abstract::The FMR1 gene, associated with fragile X syndrome, has recently been cloned and the sequence of partial cDNA clones is known. We have determined additional cDNA sequences both at the 5' and 3' end. We have characterized the expressed gene by means of RT-PCR in various tissues and have found that alternative splicing t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.4.399
更新日期:1993-04-01 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::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::XX males and XY females have a sex reversal disorder which can be caused by an abnormal interchange between the X and the Y chromosomes. We have isolated and characterized a novel gene on the Y chromosome, PRKY. This gene is highly homologous to a previously isolated gene from Xp22.3, PRKX, and represents a member of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.11.1985
更新日期:1997-10-01 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin. Several downstream consequences of dystrophin deficiency are triggers of endoplasmic reticulum (ER) stress, including loss of calcium homeostasis, hypoxia and oxidative stress. During ER stress, misfolded prote...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu249
更新日期:2014-10-15 00:00:00
abstract::Age-related macular degeneration (AMD) is a progressive neurodegenerative disease, which affects quality of life for millions of elderly individuals worldwide. AMD is associated with a diverse spectrum of clinical phenotypes, all of which include the death of photoreceptors in the central part of the human retina (cal...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddm212
更新日期:2007-10-15 00:00:00
abstract::Genome-wide association studies and, more recently, next-generation sequencing studies have accelerated the investigation of complex human traits by providing a wealth of association data linking genetic variants to diseases and other phenotypic traits. These data promise to transform our understanding of the molecula...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/dds363
更新日期:2012-10-15 00:00:00
abstract::NPHP4 mutations cause nephronophthisis, an autosomal recessive cystic kidney disease associated with renal fibrosis and kidney failure. The NPHP4 gene product nephrocystin-4 interacts with other nephrocystins, cytoskeletal and ciliary proteins; however, the molecular and cellular functions of nephrocystin-4 have remai...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr214
更新日期:2011-08-15 00:00:00
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
更新日期:2017-04-15 00:00:00
abstract::An improved understanding of the expression of the cystic fibrosis gene (CFTR) will assist our approach to preventing the organ damage caused by cystic fibrosis (CF). We have studied the expression of CFTR in human fetal tissues at different gestational ages using in situ hybridization to detect CFTR mRNA. CFTR was pr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.3.219
更新日期:1993-03-01 00:00:00
abstract::We examined the imprinting status of the insulin-like growth factor II gene (IGF2) in a series of 20 human breast disease samples to determine if disrupted imprinting (as evidenced by biallelic expression), was a demonstrable mechanism of altered gene expression. These samples included benign (n = 7) and malignant bre...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.8.1123
更新日期:1996-08-01 00:00:00
abstract::Huntington's disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency questi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa001
更新日期:2020-03-13 00:00:00
abstract::Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adol...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv465
更新日期:2016-01-15 00:00:00
abstract::Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genom...
journal_title:Human molecular genetics
pub_type: 杂志文章,meta分析
doi:10.1093/hmg/ddu150
更新日期:2014-08-15 00:00:00