Xueying Zhou

The levels of bone turnover markers in Chinese postmenopausal women: Peking Vertebral Fracture study.

Objective:The aim of this study was to evaluate serum N-aminoterminal propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (&bgr;-CTX), and vitamin D status in healthy Chinese postmenopausal women. The study was also designed to investigate their possible relationships with osteoporosis phenotypes. Methods:A community-based population of 1,724 postmenopausal women in Beijing was randomly selected. Serum bone turnover markers and 25-hydroxyvitamin D [25(OH)D] were tested by an automated Roche electrochemiluminescence system. Dual-energy x-ray absorptiometry was used to measure bone mineral density (BMD). Results:The mean (SD) values of serum &bgr;-CTX and P1NP were 0.439 (0.210) and 56.7 (27.9) ng/mL, respectively. The 25(OH)D level of postmenopausal women in Beijing was remarkably low (13.2 ± 5.4 ng/mL). Serum &bgr;-CTX and P1NP levels were negatively correlated with BMDs of lumbar spine, femoral neck, and total hip (all P < 0.01). The cubic regression model better fitted the relationships of BMD and bone turnover markers. Serum &bgr;-CTX levels were significantly higher in women with sustained osteoporotic fracture or vertebral fracture (P = 0.006 and 0.012, respectively). No association between P1NP and fracture or vertebral fracture was detected. The same situation applied to 25(OH)D. 25(OH)D was negatively correlated with &bgr;-CTX and P1NP (r = −0.073 and −0.088, P = 0.002 and <0.001, respectively). Conclusions:Serum &bgr;-CTX and P1NP levels were negatively correlated with BMD. &bgr;-CTX was significantly higher in postmenopausal women with sustained fracture or vertebral fracture. Vitamin D deficiency was highly prevalent in postmenopausal women in Beijing.

Three Novel Mutations of the PHEX Gene in Three Chinese Families with X-linked Dominant Hypophosphatemic Rickets

X-linked dominant hypophosphatemia (XLH, OMIM307800), the most prevalent form of inherited rickets in humans, is a dominant disorder of phosphate homeostasis characterized by growth retardation, rachitic and osteomalacic bone disease, hypophosphatemia, and renal phosphate wasting. The gene responsible for XLH was identified by positional cloning and designated PHEX (formerly PEX) to depict a phosphate-regulating gene homologous with endopeptidases on the X chromosome. Recently, extensive mutation analysis of the PHEX gene has revealed a wide variety of gene defects in XLH. The ethnic distribution of the mutations is very widespread but only a few mutations in Chinese have been reported. To analyze the molecular basis in three unrelated Chinese families with XLH, we determined the nucleotide sequence of the PHEX gene and fibroblast growth factor 23 (FGF23) gene of affected members. The serum FGF23 concentrations of these patients with XLH were also measured. Three different novel mutations were observed in these three families: one deletion mutation c.264delG causing p.W88 X; one missense mutation c.1673C>G causing p.P558A; one nonsense mutation c.1809G>A causing p.W603 X. Serum concentration of FGF23 in XLH patients of these three families was significantly higher than normal. The results suggest that PHEX gene mutations were responsible for XLH in these patients and these mutations may contribute to a higher serum FGF23 level.

Novel and Recurrent Mutations of WISP3 in Two Chinese Families with Progressive Pseudorheumatoid Dysplasia

Background The WNT1-inducible signaling pathway protein 3 (WISP3), which belongs to the CCN (cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed) family, is a secreted cysteine-rich matricellular protein that is involved in chondrogenesis, osteogenesis and tumorigenesis. WISP3 gene mutations are associated with progressive pseudorheumatoid dysplasia (PPD, OMIM208230), an autosomal recessive genetic disease that is characterized by the swelling of multiple joints and disproportionate dwarfism. Methodology/Principal Findings Four PPD patients from two unrelated Chinese families were recruited for this study. The clinical diagnosis was confirmed by medical history, physical examinations, laboratory results and radiological abnormalities. WISP3 mutations were detected by direct DNA sequence analysis. In total, four different mutations were identified, which consisted of two missense mutations, one deletion and one insertion that spanned exons 3, 5 and 6 of the WISP3 gene. One of the missense mutations (c.342T>G/p.C114W) and a seven-base pair frameshift deletion (c.716_722del/p.E239fs*16) were novel. The other missense mutation (c.1000T>C/p. S334P) and the insertion mutation (c.866_867insA/p.Q289fs*31) had previously been identified in Chinese patients. All four cases had a compound heterozygous status, and their parents were heterozygous carriers of these mutations. Conclusions/Significance The results of our study expand the spectrum of WISP3 mutations that are associated with PPD and further elucidate the function of WISP3.

Novel mutations of CYP27B1 gene lead to reduced activity of 1α-hydroxylase in Chinese patients.

Pseudovitamin D-deficiency rickets (PDDR) is an autosomal recessive disorder resulting from a defect in renal 25-hydroxyvitamin D 1α-hydroxylase, the key enzyme in the pathway of vitamin D metabolism. We identified ten different mutations in the 1α-hydroxylase gene (CYP27B1) in eight Chinese families with PDDR by DNA-sequence analysis. Six of them are novel missense mutations: G57V, G73W, L333F, R432C, R459C, and R492W; three are novel deletion mutations: c48-60del, c1310delG, and c1446delA; and an insertion mutation c1325-1332insCCCACCC reported previously. Functional assay revealed that the missense mutants identified in this study retain 5.5-12.1% 1α-hydroxylase activity of the wild type. The study describes nine novel mutations in addition to 37 known mutations of CYP27B1 gene and shows the correlation between these mutations and the clinical findings of 1α-hydroxylase deficiency.

Germinal mosaicism of GATA3 in a family with HDR syndrome

Germinal Mosaicism of GATA3 in a Family With HDR Syndrome Yue Sun, Weibo Xia,* Xiaoping Xing, Mei Li, Ou Wang, Yan Jiang, Yu Pei, Ping Ye, Huaicheng Liu, Yingying Hu, Xunwu Meng, and Xueying Zhou Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China Department of Endocrinology, Second Artillery Forces General Hospital, People’s Liberation Army, Beijing, China Dalian Red Cross Blood Center, Dalian, Liaoning Province, China

A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder inherited in an autosomal recessive fashion and characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH was recently mapped to chromosome 9q34, which contains the gene SLC34A3 which encodes the renal proximal tubular sodium-phosphate cotransporter NaPi-IIc. Here we describe a 29-year-old man with a history of childhood rickets who presented with increased renal phosphate clearance leading to hypophosphatemia, hypercalciuria, low serum parathyroid hormone (PTH), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and recurrent nephrolithiasis. We performed a mutation analysis of SLC34A3 (exons and adjacent introns) of the proband and his parents to determine if there was a genetic contribution. The proband proved to be compound heterozygous for two missense mutations in SLC34A3: one novel mutation in exon 7 c.571G>C (p.G191R) and one previously identified mutation in exon 13 c.1402C>T (p.R468W). His parents were both asymptomatic heterozygous carriers of one of these two mutations. We also performed an oral phosphate loading test and compared serum phosphate, intact PTH, and intact fibroblast growth factor 23 (iFGF23) in this patient versus patients with other forms of hypophosphatemic rickets, the results of which further revealed that the mechanism of hypophosphatemia in HHRH is independent of FGF23. This is the first report of HHRH in the Chinese population. Our findings of the novel mutation in exon 7 add to the list of more than 20 reported mutations of SLC34A3.

A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study.

The Matrilin3 gene (MATN3) encodes an extracellular matrix protein, which modulates chondrocyte differentiation. The aim of this study was to test for association of MATN3 polymorphisms with bone mineral density (BMD), fracture, vertebral fracture, bone turnover or 25-hydroxyvitamin D [25(OH)D] in postmenopausal women. A community-based population of 1488 postmenopausal women was randomly selected in Beijing. The history of fracture and vertebral fracture was obtained via questionnaire and vertebral X-ray respectively. BMD of lumbar spine (2-4), femoral neck and total hip were measured by dual energy X-ray absorptiometry. Serum N-terminal procollagen of type 1 collagen (P1NP), β-isomerized type I collagen C-telopeptide breakdown products (β-CTX) and 25(OH)D were quantified. Binary logistic regression revealed that Haplotype-4 was significantly associated with vertebral fracture risk in both additive model (p=0.023, OR=1.521) and dominant model (p=0.028, OR=1.623). The significance remained after 10,000 permutation tests to correct multiple testing (p=0.042). Re-selected age matched vertebral fracture case-control groups revealed similar associations in additive model (p=0.014, OR=1.927, 95%CI=1.142-3.253) and in dominant model (p=0.011, OR=2.231, 95%CI=1.200-4.148). However, no significant association was found between MATN3 polymorphisms and serum β-CTX, P1NP, 25(OH)D levels, or BMD. In linear regression, Haplotype-2 approached marginal significance in association with femoral neck BMD T-score (p=0.050), but this would account for only 0.2% of BMD variation in our sample. This study suggests that Haplotype-4 of MATN3 is associated with vertebral fracture risk independent of BMD in Chinese postmenopausal women. Efforts should be made to replicate our finding in other, similar and ethnically diverse, populations.

Mutation update and short-term outcome after treatment with active vitamin D 3 in Chinese patients with pseudo-vitamin D-deficiency rickets

Summary Pseudovitamin D-deficiency rickets is a rare disease which is caused by CYP27B1. In this study, we identified 9 mutations in 7 PDDR patients. In addition, we observed the response to long-term treatment of calcitriol in 15 Chinese patients with PDDR, which showed that the biochemical abnormalities had been corrected satisfactorily after 1-year treatment.