Association of Multiple Nucleotide Variations in the Pituitary Glutaminyl Cyclase Gene (<i>QPCT</i>) With Low Radial BMD in Adult Women

Ezura, Yoichi; Kajita, Mitsuko; Ishida, Ryota; Yoshida, Shoko; Yoshida, Hideyo; Suzuki, Takao; Hosoi, Takayuki; Inoue, Satoshi; Shiraki, Masataka; Orimo, Hajime; Emi, Mitsuru

doi:10.1359/jbmr.040324

Cited by 39 publications

(28 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The protective function of the QPCT gene for hypothalamic/pituitary peptide hormones makes it a potential candidate gene. Ezura et al (2004) previously reported that the QPCT gene affects BMD among postmenopausal women in the Japanese population. In this study, we independently replicated the association between the variant rs3770748 and BMD in the Chinese population.…”

Section: Discussionmentioning

confidence: 98%

The association of common polymorphisms in the QPCT gene with bone mineral density in the Chinese population

Huang

Kung

2007

J Hum Genet

View full text Add to dashboard Cite

Evidence of the linkage of chromosome 2p to bone mineral density (BMD) has previously been reported in multiple populations. However, the identification of the BMD quantitative trait loci (QTL) gene at chromosome 2p remains a challenge. We performed a gene-wide and tag single nucleotide polymorphism (SNP)-based association study of four positional and functional candidate genes (CALM2, CYP1B1, QPCT, and POMC) in a sample of 1,243 cases and matched controls. Thirteen HapMap tag SNPs were selected and genotyped by using the highthroughput Sequenom genotyping platform. Binary logistic regression analyses were performed to test for associations between each SNP genotype and BMD. Haplotype association analyses were performed by WHAP. The rs3770748 within the QPCT gene showed a significant association with spine BMD in both singlemarker (P = 0.002) and haplotype association analyses (P = 0.0482 for the global test; P = 0.00092 for the haplotype-specific test). Subgroup analysis revealed that the effect was primarily driven by an association in the postmenopausal women, presumably suggesting that the rs3770748 affects postmenopausal bone loss rather than peak bone mass. Our results suggest that QPCT may be the QTL gene at chromosome 2p for spine BMD variation in the Chinese population.

show abstract

Section: Discussionmentioning

confidence: 98%

The association of common polymorphisms in the QPCT gene with bone mineral density in the Chinese population

Huang

Kung

2007

J Hum Genet

View full text Add to dashboard Cite

show abstract

“…13 In human disease, compelling evidence suggests an involvement of QC in conditions such as rheumatoid arthritis, osteoporosis and Alzheimer's disease (AD). 14,15 Significant amounts of beta-amyloid (Aβ) peptides, deposited in amyloid plaques of AD, are N-terminally modified to possess a pGlu residue originating from glutamate cyclization. 16,17 .…”

Section: Introductionmentioning

confidence: 99%

Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery

Cynis

Rahfeld

Stephan

et al. 2008

Journal of Molecular Biology

View full text Add to dashboard Cite

“…The gene encoding QC (QPCT) lies on chromosome 2p22.3. Within the region, 13 SNPs were analyzed and showed a striking correlation with osteoporosis susceptibility in adult women (11). Of these SNPs, R54W presents the most prominent association with osteoporosis statistically, which was proposed to affect the pathogenesis through the hypothalamus-pituitary-gonadal axis (11).…”

mentioning

confidence: 99%

Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation

Huang

Liu

Cheng

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

105

120

View full text Add to dashboard Cite

N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis and amyloidotic diseases. This N-terminal cyclization reaction, once thought to proceed spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase (QC). To probe this important but poorly understood modification, we present here the structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors. The structure reveals an ␣͞␤ scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site displays alternate conformations due to the different indole orientations of Trp-207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. Our results provide a structural basis for the rational design of inhibitors against QC-associated disorders.crystallography ͉ intramolecular cyclization ͉ posttranslational modification ͉ Alzheimer's disease ͉ aminopeptidase N -terminal pyroglutamate (pGlu) formation from its glutaminyl precursor is an important posttranslational or cotranslational event in the processing of numerous bioactive neuropeptides, hormones, and cytokines during their maturation in the secretory pathway. These regulatory peptides require the N-terminal pGlu to develop the proper conformation for binding to their receptors and͞or to protect the N termini of the peptides from exopeptidase degradation (1, 2). Previously, this Nterminal cyclization reaction was thought to proceed spontaneously, until the glutaminyl cyclases (QCs) were identified as catalysts that are responsible for this posttranslational modification (3, 4).QCs (EC 2.3.2.5) are acyltransferases that have been identified in both animal and plant sources (3-5). They are abundant in mammalian neuroendocrine tissues, such as hypothalamus and pituitary (4, 6), and are highly conserved from yeast to human. Animal QCs were shown to have distinct structure and protein stability from plant QCs despite their similar molecular masses [i.e., 33-40 kDa (5, 7)]. No bacterial QCs have been reported thus far; however, the mammalian QCs were predicted to exhibit remarkable homology to the bacterial double-zinc aminopeptidases (8, 9).In humans, several genetic diseases, such as osteoporosis, a multifactorial hormonal disease that is characterized by reduced bone mass and microarchitectural deterioration of bone tissue (10), appear to result from mutations of the QC gene. The gene encoding QC (QPCT) lies on chromosome 2p22.3. ...

show abstract

Association of Multiple Nucleotide Variations in the Pituitary Glutaminyl Cyclase Gene (QPCT) With Low Radial BMD in Adult Women

Cited by 39 publications

References 27 publications

The association of common polymorphisms in the QPCT gene with bone mineral density in the Chinese population

The association of common polymorphisms in the QPCT gene with bone mineral density in the Chinese population

Isolation of an Isoenzyme of Human Glutaminyl Cyclase: Retention in the Golgi Complex Suggests Involvement in the Protein Maturation Machinery

Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation

Contact Info

Product

Resources

About