[Show abstract][Hide abstract] ABSTRACT: X-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia.
PLoS ONE 05/2014; 9(5):e97830. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: The aims of this study were to (1) evaluate the association of serum sclerostin with bone mineral density (BMD) and markers of bone metabolism in postmenopausal Chinese women and (2) observe the relationships of single nucleotide polymorphisms (SNPs) within the sclerostin (SOST) gene with serum sclerostin, BMD, and markers of bone metabolism. Design: A cross-sectional study was conducted with 703 postmenopausal Chinese women. Ten tagging SNPs (rs1234612, rs1513670, rs1634330, rs1708635, rs2023794, rs7220711, rs74252774, rs851057, rs851058, and rs865429) of the SOST gene were genotyped. Serum sclerostin and markers of bone metabolismwere measured, including serum intact parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], procollagen type 1 N-terminal propeptide (P1NP), and β-CrossLaps of type I collagen containing cross-linked C-telopeptide (β-CTX). The BMD of the lumbar spine and proximal femur were measured by dual-energy X-ray absorptiometry. Results: Serum sclerostin was positively correlated with BMD at lumbar spine, femoral neck, total hip and with serum 25(OH)D (all P<0.01), but negatively correlated with β-CTX (P<0.01). The significant relationships between serum sclerostin and BMD and with serum β-CTX persisted even after adjustments for age, BMI and serum 25(OH)D (all P<0.01). However, there was no correlation between serum sclerostin and age or serum P1NP. We failed to identify a significant association between the SNP, haplotypes of SOST and BMD, serum sclerostin, or markers of bone metabolism. Conclusion: Our results suggested that serum sclerostin was positively correlated with the BMD at lumbar spine, femoral neck, total hip and with serum 25(OH)D but was negatively correlated with serum β-CTX. Genetic polymorphisms of SOST may not be a major contributor to variations in the serum sclerostin or BMD in postmenopausal Chinese women.
The Journal of Clinical Endocrinology and Metabolism 04/2014; · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dent disease comprises a group of X-linked recessive inherited renal tubular disorders, the symptoms of which include low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, and progressive renal failure. We sought to characterize the clinical manifestations and to identify the mutations associated with this disease in Chinese patients. In total, 155 DNA samples were collected from one affected individual, four of his family members, and 150 healthy donors. All 12 exons and the exon-intron boundaries of the CLCN5 gene were amplified and directly sequenced in this Chinese family. The proband demonstrated osteomalacia, which had resulted in more than 10 fractures, LMWP, and renal failure. A single base 'G' deletion at nucleotide 246 (c. 246delG) was identified in exon 5 of the CLCN5 gene in this patient, resulting in a frame shift mutation (fsX) that changed the Threonine (Thr) residue in position 83 to Proline (Pro). The proband's mother was found to be a carrier of this mutation. The present study suggests that a novel frameshift mutation (c. 246delG) in exon 5 of the CLCN5 gene is responsible for Dent disease in this case. Our findings also expand the known spectrum of CLCN5 mutations.
[Show abstract][Hide abstract] ABSTRACT: Abstract Objectives: Mutations in the CYP27B1 gene, which encodes vitamin D 1α-hydroxylase, are the genetic basis of vitamin D-dependent rickets type 1A (VDDR1A, MIM 264700). The aim of this study was to investigate a novel CYP27B1 mutation and its clinical manifestations. Methods: VDDR1A was diagnosed based on clinical presentation, a physical examination, bone characteristics on an X-ray, and laboratory results. A molecular model of the CYP27B1 protein was constructed using the SWISS-MODEL server and Swiss-PdbViewer. Results: We sequenced the CYP27B1 gene in a 5-year-old male child who presented with growth retardation and a history of frequent hand, leg, and perioral twitching since the age of 12 months. We identified a compound heterozygous mutation consisting of two missense mutations: one in exon 7 (R389C [c.1165C>T]) and one in exon 8 (R459C [c.1375C>T]). We used the wild-type CYP27B1 as a receptor and calcidiol as a ligand to predict the interaction between the R459 site and calcidiol. According to the predicted structure, the wild-type R459 residue localizes to the pocket where CYP27B1 binds to its ligand. Conclusions: According to the Human Gene Mutation Database, the compound heterozygous mutation identified in our patient is novel and has not yet been reported in the literature. This mutation provides a new basis for further research on VDDR1A and for the development of clinical diagnostics.
[Show abstract][Hide abstract] ABSTRACT: Aim:PRD1-BF-1-RIZ1 homologous domain containing protein-16 (PRDM16) is a cell-autonomous transcriptional component that stimulates the development of brown fat cells. The aim of this study was to investigate the contribution of genetic variants of PRDM16 to obesity-related phenotype variations in Chinese.Methods:A total of 3204 subjects (consisting of 400 male-offspring nuclear families, 401 female-offspring nuclear families, and 729 unrelated older males) were recruited. Ten tag single nucleotide polymorphisms (SNPs) within the PRDM16 gene were genotyped using multiplex quantitative real-time PCR by Taqman assay. Body compositions were measured by dual-energy X-ray absorptiometry (DXA). The associations of the SNPs with the obesity-related phenotypes were analyzed using the quantitative transmission disequilibrium test (QTDT), GLM-ANOVA and PLINK statistical methods.Results:Rs2236518 was the only SNP that was associated with BMI in young (aged 20-40 years) males (P=0.011) using QTDT, and in the older men (aged 50-80 years) (P=0.003) using GLM-ANOVA. No significant associations were detected in the females. Nor was a relationship found between any haplotype and obesity-related phenotypes. When PLINK was used, no significant relationship was detected between 10 SNPs and obesity-related phenotypes in any of the studied cohorts.Conclusion:Rs2236518 is associated with BMI in the young males (using QTDT), and the older males (using GLM-ANOVA).However, the result is not confirmed using PLINK. The discrepancy needs to be further addressed.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the clinical characteristics and major causative gene in pediatric patients with Camurati‑Engelmann disease (CED). Biochemical and radiographic examinations, bone scintigraphy and genetic analyses were performed in two affected males and their parents. The two patients experienced waddling gait, muscular weakness and growth developmental delay. X-ray radiography revealed typical fusiform thickening of the diaphyseal portions of the long bones. The abnormal uptake of tracer Tc-99m was visualized in the skull and both sides of the upper humeri, ulnas, radii, femurs and tibias using bone scintigraphy. Serum levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) and the bone resorption marker β‑isomerized C-terminal cross-linked telopeptide of type I collagen (β-CTX) in the 6-year-old patient were significantly increased compared with the normal value range, while only the β-CTX levels were elevated in the 16-year-old patient. A heterozygous missense mutation p.Arg218Cys in exon 4 of the transforming growth factor β1 (TGFβ1) gene was detected in the two patients, while their parents had normal wild‑type genotypes. In conclusion, the p.Arg218Cys mutation was shown to contribute to the clinical phenotypes in two pediatric patients with CED. The results of this study suggest that abnormal bone turnover marker levels, typical radiological findings and mutations in the TGFβ1 gene are three important factors in the diagnosis of sporadic CED cases.
Molecular Medicine Reports 03/2013; · 1.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IntroductionInclusion-body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD), designated as IBMPFD, is a rare, autosomal dominant disorder (MIM 605382). IBMPFD is caused by mutations in the gene that encode valosin-containing protein (VCP). We investigated a Chinese family in which multiple members were diagnosed with PDB and suffered from weakness of the limbs. However, no members of this family were diagnosed with FTD. We made a preliminary diagnosis of PDB, but failed to identify an SQSTM1 mutation in any of the patients. We used whole-exome sequencing to identify the pathogenic gene mutation affecting the Chinese male proband.Materials and methodsAltogether, 254 subjects, including one 56-year-old male proband, four affected, related individuals and additional nine family members from a non-consanguineous Chinese family, and 240 healthy donors were recruited and genomic DNA was extracted. All eight exons and the exon–intron boundaries of the SQSTM1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced in five patients (II13, II4, II5, II8, II9). Using whole-exome sequencing, we identified a novel mutation in VCP as the disease-causing mutation. We confirmed the result by sequencing a 500-bp region of the promoter and the coding region of VCP in all 254 of the participants using Sanger sequencing.ResultsNo mutation in the SQSTM1 gene was identified in the five patients examined using direct Sanger sequencing. However, through whole-exome sequencing we were able to identify a novel missense mutation in exon 3 of the VCP gene (p.Gly97Glu) in the Chinese male proband. This mutation was confirmed using Sanger sequencing. The proband, four affected individuals and three unaffected individuals carried this mutation. We were able to correctly diagnose the patients with atypical IBMPFD. Structural analysis of the p.Gly97Glu mutation in the VCP protein showed that the affected amino‐acid is located in the interface of the protein. This abnormality may therefore interfere with protein function.Conclusions
This is the first report of a family from China with IBMPFD. A novel VCP mutation was found as the cause of atypical IBMPFD in a Chinese family. Our findings confirm that VCP gene mutations can be a pathogenic cause of IBMPFD.
[Show abstract][Hide abstract] ABSTRACT: Objective Osteosclerosis (OMIM: 144750) is a type of autosomal dominant bone disease caused by a mutation in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. The case of a Chinese family with two affected individuals is reported in the present study in order to investigate the clinical characteristics and virulence genes of this sclerosing bone disorder. Methods Biochemical and radiographic examinations and bone mineral density (BMD) and genetic analyses were performed in two patients and eight other family members. Results The 40-year-old proband (II-1) and her 64-year-old mother (I-2) both had chronic lumbodorsal pain, an elongated mandible and torus palatinus in the center of the hard palate. No fractures were observed in any of the family members. Skull, mandibular and pelvic X-rays in each of the two patients revealed thickened cranial plates, an enlarged sella turcica, an elongated mandible and cortical thickening of the long bones. The BMD values of the two patients was significantly higher than the standard age- and sex-matched adult mean reference values. Both patients had higher serum sclerostin levels, while their renal function markers and serum calcium, phosphonium, parathyroid hormone (PTH) and 25(OH)D levels were within the normal ranges. The heterozygous missense mutation p.Ala242Thr in exon 4 of the LRP5 gene was detected in the two patients, while the other family members and 200 healthy donors had normal wild-type genotypes. Conclusion The A242T mutation in the LRP5 gene resulted in a high bone mass phenotype with an elongated mandible and torus palatinus in this osteosclerotic family.
Internal Medicine 01/2013; 52(2):187-92. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The reference ranges of bone turnover markers (BTMs) were important during the treatment of osteoporosis, and the associations with bone mineral density (BMD) were controversial. The aim of this study was to establish the reference ranges of N-terminal procollagen of type l collagen (P1NP), osteocalcin (OC), and beta C-terminal cross-linked telopeptides of type I collagen ( β -CTX) in Shanghai area and to investigate the relationships between BTMs and BMD in postmenopausal women. 2,799 subjects recruited in Shanghai City were measured BTMs to establish the reference ranges. Additional 520 healthy postmenopausal women were also measured BTMs, these women measured BMD in addition. BTMs were measured using the Roche electrochemiluminescence system. We used the age range of 35 to 45-year-olds to calculate reference intervals. The reference range of OC was 4.91 to 13.90 ng/mL for women and 5.58 to 16.57 ng/mL for men, P1NP was 13.72 to 32.90 ng/mL for women and 16.89 to 42.43 ng/mL for men, and β -CTX was 0.112 to 0.210 ng/mL for women and 0.100 to 0.378 ng/mL for men. BTMs significantly negatively correlated with lumbar spine and femoral and total hip in postmenopausal women (Betastd = -0.157 ~ -0.217, P < 0.001). We established the normal reference ranges of P1NP, OC, and β -CTX in the Shanghai area. This study also found that BTMs correlated with BMD and suggested that BTMs were the key determining factors of early BMD decreases.
International Journal of Endocrinology 01/2013; 2013:513925. · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the skeletal effects and the potential underlying mechanisms of treatment with two thiazolidinediones (rosiglitazone and pioglitazone) or metformin in insulin-resistant mice, 24 female, 12-week-old C57BL6J ob/ob mice were evaluated according to the following treatment groups for 6 weeks: placebo group, pioglitazone group (Pio), rosiglitazone group (Rosi), and metformin group (Met). Bone mineral density (BMD), bone microarchitecture, bone histomorphometry, and expression of three phenotype-specific gene markers, including bone morphogenetic protein 2 (Bmp2), runt-related transcription factor 2 (Runx2), and fatty acid-binding protein 4 (Fabp4), were compared across the four groups. At the femur, the Met group had the highest BMD (0.084 ± 0.001 g/cm(2)) and trabecular bone volume/total volume (0.644 ± 0.018 %) and the lowest trabecular spacing (Tb.Sp.) (0.143 ± 0.008 μm), whereas the Rosi group had lower BMD (0.076 ± 0.003 g/cm(2)) and a relatively higher degree of Tb.Sp. (0.173 ± 0.024 μm). A histomorphometric analysis revealed that in the Rosi group the number of adipocytes was fourfold higher than in the placebo group and fivefold higher than in the Met group, whereas the highest osteoid width and mineral apposition rate were found in the Met group (49.88 ± 48.53 μm and 4.46 ± 1.72 μm/day). Furthermore, the Rosi group displayed the highest level of Fabp4 gene expression, which was accompanied by normal expression levels of Bmp2 and Runx2. Seemingly, metformin is a bone-friendly antidiabetic drug. Rosiglitazone had adverse effects on the skeleton at the trabecular bone even in insulin-resistant mice, whereas no evidence of adverse effects was found for pioglitazone.
Journal of Bone and Mineral Metabolism 08/2012; · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lipoxygenase (LOX) is one of the major metabolic enzymes for arachidonic acid, which has been reported to be associated with many postmenopausal and many hormone-related diseases. In rats, selective inhibition of the LOX pathway led to defective ovulation. However, little is known about the association of the LOX-related genes with menstruation in women. In this study, we investigated the possible association of two key gene (ALOX12 and ALOX15) polymorphisms with age of menarche and menopause in Chinese women.
Six tagging single nucleotide polymorphisms (SNPs) of ALOX12 and five SNPs of ALOX15 were genotyped. The association of single SNPs and haplotypes in two candidate genes and age at menarche (AAM) variation was tested in 401 Chinese nuclear families using the quantitative transmissing disequilibrium test. Furthermore, the association between these SNPs and haplotypes and age at natural menopause (AANM) in 710 postmenopausal Chinese women was measured.
Using family- and population-based statistical procedures, significant association was found between SNPs rs312462 in ALOX12 and AAM in nuclear families (P = 0.043), and three SNPs (rs2292350, rs312470, and rs312462) in ALOX12 were significantly associated with AANM in postmenopausal women (P = 0.012, P = 0.045, and P = 0.033, respectively). Haplotype analyses corroborated our single SNP results (P = 0.030). However, we failed to find a significant association between ALOX15 gene polymorphisms and AAM as well as AANM (P > 0.05).
Our present results suggest that genetic variations in ALOX12 are associated with both the onset and cessation of menstruation in Chinese women living in Shanghai.
Menopause (New York, N.Y.) 06/2012; 19(9):1029-36. · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested that changes in hip geometry increase the risk of hip fracture. The aim of this study was to identify whether body composition were associated with hip geometry or bone mineral density (BMD) in a large sample of Chinese people. A total of 2072 subjects aged 20-79yr (including 700 males and 1372 females) were selected. The following measurements were taken: lumbar spine (L1-4); proximal femur BMD; lean mass (LM); fat mass (FM); and hip geometric parameters, including hip axis length (HAL), cross-sectional moment of inertia (CSMI), cross-sectional area (CSA), neck-shaft angle, and femur strength index (SI) by dual-energy X-ray absorptiometry. FM and LM were positively correlated with HAL, CSMI, and CSA, and negatively correlated with SI in both men and women. Multiple regression analysis showed that leg LM contributions to HAL, CSMI, and CSA variance were 12.6-37.6%. Compared with FM, LM was generally more strongly related to hip geometry and BMD in young and old men and women. Body composition was a good predictor for hip geometry parameter variation and BMD variation.
Journal of Clinical Densitometry 04/2012; · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To increase awareness of the rarity of Paget's disease of bone (PDB) in the Chinese population, we characterized the clinical manifestations and features of 13 Chinese sporadic PDB patients. The clinical features of our Chinese PDB patients show similarities with cases reported in Western countries. The most common lesion sites were the pelvis, femur, and tibia; the next most common lesion sites were the spine and skull. Most patients had a higher serum alkaline phosphatase (ALP) level. Treatment with bisphosphonates was effective. In addition, we screened for PDB-causing mutations and performed a functional analysis in an attempt to elucidate the molecular pathogenesis of PDB. A total of 216 persons, including 13 sporadic PDB patients, three unaffected relatives of 1 patient, and 200 healthy donors, were recruited. All eight exons and exon-intron boundaries of the SQSTM1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced. We identified a 53-year-old man who harbored a heterozygous T-to-C transversion at position 1250 in exon 8 (1250T > C), which resulted in a methionine-to-threonine (ATG > ACG) substitution at codon 404 (M404T). The M404T mutant SQSTM1 protein exhibited increased NF-κB activation and drove a significantly increased number of osteoclast-like cells (OLCs) that formed in response to RANKL and an increased number of OLC nuclei. This is the first report of an SQSTM1 genetic mutation that contributes to the pathogenesis of PDB in Chinese patients. These results may partially explain the mechanism by which this SQSTM1 mutation contributes to the pathogenesis of sporadic PDB in Chinese patients.
Journal of Bone and Mineral Metabolism 04/2012; 30(5):525-33. · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myostatin gene is a member of the transforming growth factor-β (TGF-β) family that negatively regulates skeletal muscle growth. Genetic polymorphisms in Myostatin were found to be associated with the peak bone mineral density (BMD) in Chinese women. The purpose of this study was to investigate whether myostatin played a role in the normal variation in peak BMD, lean mass (LM), and fat mass (FM) of Chinese men.
Four hundred male-offspring nuclear families of Chinese Han ethnic group were recruited. Anthropometric measurements, including the peak BMD, body LM and FM were measured using dual-energy X-ray absorptiometry (DXA). The single nucleotide polymorphisms (SNPs) studied were tag-SNPs selected by sequencing. Both rs2293284 and +2278GA were genotyped using TaqMan assay, and rs3791783 was genotyped with PCR-restriction fragment length polymorphism (RFLP) analysis. The associations of the SNPs with anthropometric variations were analyzed using the quantitative transmission disequilibrium test (QTDT).
Using QTDT to detect within-family associations, neither single SNP nor haplotype was found to be associated with peak BMD at any bone site. However, rs3791783 was found to be significantly associated with fat mass of the trunk (P<0.001). Moreover, for within-family associations, haplotypes AGG, AAA, and TGG were found to be significantly associated with the trunk fat mass (all P<0.001).
Our results suggest that genetic variation within myostatin may play a role in regulating the variation in fat mass in Chinese males. Additionally, the myostatin gene may be a candidate that determines body fat mass in Chinese men.
[Show abstract][Hide abstract] ABSTRACT: Genetic variation in ALOX12, which encoded human 12-lipoxygenase, was found to be associated with fat mass in young Chinese men. The objective of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) and haplotypes in the ALOX15 gene and obesity-related phenotypes in Chinese nuclear families with male offspring.
We recruited 1,296 subjects from 427 nuclear families with male offspring and genotyped five SNPs (rs9894225, rs748694, rs2619112, rs2619118, and rs916055) in the ALOX15 gene locus. The total fat mass (TFM), trunk fat mass (tFM), leg fat mass (LFM) and arm fat mass (AFM) were measured using dual-energy X-ray absorptiometry (DXA). The percentage of fat mass (PFM) was the ratio of TFM and body weight. The association between SNPs and haplotypes of ALOX15 and obesity-related phenotypic variation was measured using quantitative transmission disequilibrium test (QTDT).
Using QTDT to measure family-based genetic association, we found that rs916055 had a statistically significant association with PFM (P=0.038), whereas rs916055 had a marginal but statistically insignificant association with tFM (P=0.093). The multiple-parameter 1000 permutations test agreed with the family-based association results: both showed that rs916055 had a statistically significant association with PFM (P=0.033).
rs916055 in ALOX15 gene was significantly associated with the percentage of fat mass in Chinese nuclear families with male offspring in the family-based association study using QTDT approach.