Plastin 3基因多态性与绝经后中国妇女骨密度及骨折的相关性研究
发布时间：2018-11-10 18:20
【摘要】：目的:Plastin 3(PLS3)基因位于X染色体上,编码肌动蛋白结合蛋白网素3(plastin3),该蛋白负责对肌动蛋白细胞骨架的动态装配和拆卸。在鹿特丹研究(Rotterdam study)的人群中,PLS3基因突变被证实与骨质疏松症和骨折的发生有关。因此,本研究目的是探讨PLS3基因的多态性是否与绝经后中国女性的骨质疏松性骨折的发生或低骨密度(BMD)风险相关。方法:共3661名无亲缘关系的绝经后妇女被招募,其中包括1083名骨质疏松性骨折患者和2578名健康对照者。对所有参与者的PLS3基因的六个标签单核苷酸多态性(SNP)以及在鹿特丹研究中被确认的与骨折相关的SNP(rs140121121)进行基因分型。对其中的3166名受试者进行了腰椎(L1-4),股骨颈和全髋骨密度的测定。结果:在3661名受试者中未发现rs140121121的多态性。此外,经过Bonferroni校正,未发现PLS3基因的多态性与绝经后中国妇女骨质疏松性骨折或骨密度相关联。结论:我们的研究结果表明,PLS3基因多态性与绝经后中国女性骨质疏松性骨折或低骨密度的风险无关,可见PLS3基因在骨质疏松性骨折及低骨密度风险方面所表现出来的遗传影响在不同人种的人群中并不一致。目的:通过对2例低磷酸酶血症(HPP)患者及家系进行临床分析和基因突变检测,拓展国人HPP的致病基因库,并结合文献探讨HPP的致病机制。方法:对HPP家系中的先证者和其父母亲进行生化指标检测[血常规、肝肾功能、碱性磷酸酶(ALP)、甲状旁腺素(PTH)、钙、磷等]和骨密度检测。同时对所有的研究对象进行ALPL基因全部12个外显子和外显子内含子交界区直接测序。结果:来自家系1的先证者为36岁成年男性,身高131.0cm,体重35.0kg。X线提示多发性胸腰椎骨折和骨盆畸形,生化检测发现血清ALP 27U/L。测序发现ALPL基因6号外显子532位杂合突变(c.532TC),导致ALPL成熟多肽中酪氨酸被组氨酸替代。该先证者的母亲,身高140.5cm,体重39.5kg,血清ALP30U/L,基因测序证明其也是该杂合突变携带者。而来自家系2的先证者5岁,其外祖父母为近亲结婚。该患儿身高100.0cm,体重18kg。血清ALP 55U/L[低于同年龄儿童(小于10岁)的正常值:75~344U/L],存在牙齿发育不良和脱落,有左股骨中下端骨折史。测序发现该患儿存在ALPL基因两个错义突变,其中9号外显子的c.871GA突变是Mornet在1998年报道的突变。而4号外显子269位突变(c.269AG)是一个新的错义突变,该突变导致了成熟ALPL多肽中天冬氨酸被甘氨酸所替代。该患儿的母亲亦是4号外显子c.269AG错义突变的携带者,但是其生化指标正常,无骨骼和牙齿的异常。结论:本研究发现的ALPL基因6号外显子c.532TC突变和4号外显子c.269AG突变是以往未曾报道过的新的错义突变,是上述两例HPP患者的致病基因突变。
[Abstract]:Aim: Plastin 3 (PLS3) gene is located on X chromosome and encodes actin binding protein reticulin-3 (plastin3), which is responsible for the dynamic assembly and disassembly of actin cytoskeleton. In the Rotterdam study of (Rotterdam study), mutations in the PLS3 gene have been linked to osteoporosis and fracture. Therefore, the aim of this study was to investigate whether the polymorphism of PLS3 gene was associated with the occurrence of osteoporotic fracture or the risk of low bone mineral density (BMD) in postmenopausal Chinese women. Methods: a total of 3661 unrelated postmenopausal women were recruited, including 1083 patients with osteoporotic fractures and 2578 healthy controls. Six tagged single nucleotide polymorphisms (SNP) of the PLS3 gene and SNP (rs140121121) identified in the Rotterdam study were genotyped. 3166 of the subjects were measured for lumbar (L-1-4), femoral neck and total hip bone density. Results: no polymorphism of rs140121121 was found in 3661 subjects. In addition, no association between PLS3 gene polymorphism and osteoporosis fracture or bone mineral density in postmenopausal Chinese women was found after Bonferroni correction. Conclusion: our results suggest that PLS3 gene polymorphism is not associated with the risk of osteoporosis fracture or low bone density in postmenopausal Chinese women. The genetic effects of PLS3 gene on the risk of osteoporosis fracture and low bone mineral density were not consistent among different ethnic groups. Objective: to explore the pathogenetic gene pool of Chinese HPP by clinical analysis and gene mutation detection in 2 patients and families with hypophosphatase (HPP), and to explore the pathogenesis of HPP. Methods: the biochemical indexes (blood routine examination, liver and kidney function, alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium, phosphorus, etc.) and bone mineral density (BMD) were measured in the probands and their parents of HPP families. All 12 exons and intron junctions of ALPL gene were sequenced. Results: the proband from pedigree 1 was a 36-year-old adult male with a height of 131.0 cm. The 35.0kg.X line indicated multiple thoracolumbar fractures and pelvic deformities. The serum ALP 27U / L was detected by biochemical examination. ALPL gene exon 6 was found to have a 532-position heterozygosity (c.532TC), which led to the replacement of tyrosine with histidine in mature ALPL polypeptides. The mother of the proband, who was 140.5 cm tall and 39.5 kg, was also found to be a carrier of the heterozygous mutation by serum ALP30U/L, gene sequencing. The proband, from family 2, was 5 years old, and his grandparents married close relatives. The child was 100.0 cm tall and weighed 18 kg. Serum ALP 55U/L [lower than the normal value of children of the same age (< 10 years old): 75~344U/L], dental dysplasia and exfoliation, history of fracture of left middle and lower femur. Two missense mutations in the ALPL gene were found in the patient by sequencing. The c.871GA mutation in exon 9 was reported by Mornet in 1998. Exon 4 (c.269AG) is a new missense mutation, which leads to the substitution of aspartic acid with glycine in mature ALPL polypeptides. The mother was also a carrier of c.269AG missense mutation in exon 4, but its biochemical parameters were normal and no abnormal bone and teeth were found. Conclusion: the c.532TC mutation in exon 6 of ALPL gene and the c.269AG mutation in exon 4 of ALPL gene are new missense mutations which have not been reported before. They are two pathogenetic gene mutations of HPP patients mentioned above.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R580
本文编号：2323241
[Abstract]:Aim: Plastin 3 (PLS3) gene is located on X chromosome and encodes actin binding protein reticulin-3 (plastin3), which is responsible for the dynamic assembly and disassembly of actin cytoskeleton. In the Rotterdam study of (Rotterdam study), mutations in the PLS3 gene have been linked to osteoporosis and fracture. Therefore, the aim of this study was to investigate whether the polymorphism of PLS3 gene was associated with the occurrence of osteoporotic fracture or the risk of low bone mineral density (BMD) in postmenopausal Chinese women. Methods: a total of 3661 unrelated postmenopausal women were recruited, including 1083 patients with osteoporotic fractures and 2578 healthy controls. Six tagged single nucleotide polymorphisms (SNP) of the PLS3 gene and SNP (rs140121121) identified in the Rotterdam study were genotyped. 3166 of the subjects were measured for lumbar (L-1-4), femoral neck and total hip bone density. Results: no polymorphism of rs140121121 was found in 3661 subjects. In addition, no association between PLS3 gene polymorphism and osteoporosis fracture or bone mineral density in postmenopausal Chinese women was found after Bonferroni correction. Conclusion: our results suggest that PLS3 gene polymorphism is not associated with the risk of osteoporosis fracture or low bone density in postmenopausal Chinese women. The genetic effects of PLS3 gene on the risk of osteoporosis fracture and low bone mineral density were not consistent among different ethnic groups. Objective: to explore the pathogenetic gene pool of Chinese HPP by clinical analysis and gene mutation detection in 2 patients and families with hypophosphatase (HPP), and to explore the pathogenesis of HPP. Methods: the biochemical indexes (blood routine examination, liver and kidney function, alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium, phosphorus, etc.) and bone mineral density (BMD) were measured in the probands and their parents of HPP families. All 12 exons and intron junctions of ALPL gene were sequenced. Results: the proband from pedigree 1 was a 36-year-old adult male with a height of 131.0 cm. The 35.0kg.X line indicated multiple thoracolumbar fractures and pelvic deformities. The serum ALP 27U / L was detected by biochemical examination. ALPL gene exon 6 was found to have a 532-position heterozygosity (c.532TC), which led to the replacement of tyrosine with histidine in mature ALPL polypeptides. The mother of the proband, who was 140.5 cm tall and 39.5 kg, was also found to be a carrier of the heterozygous mutation by serum ALP30U/L, gene sequencing. The proband, from family 2, was 5 years old, and his grandparents married close relatives. The child was 100.0 cm tall and weighed 18 kg. Serum ALP 55U/L [lower than the normal value of children of the same age (< 10 years old): 75~344U/L], dental dysplasia and exfoliation, history of fracture of left middle and lower femur. Two missense mutations in the ALPL gene were found in the patient by sequencing. The c.871GA mutation in exon 9 was reported by Mornet in 1998. Exon 4 (c.269AG) is a new missense mutation, which leads to the substitution of aspartic acid with glycine in mature ALPL polypeptides. The mother was also a carrier of c.269AG missense mutation in exon 4, but its biochemical parameters were normal and no abnormal bone and teeth were found. Conclusion: the c.532TC mutation in exon 6 of ALPL gene and the c.269AG mutation in exon 4 of ALPL gene are new missense mutations which have not been reported before. They are two pathogenetic gene mutations of HPP patients mentioned above.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R580
【参考文献】
相关期刊论文 前1条
1 王赎;刘建民;;骨质疏松症的全基因组关联分析进展[J];诊断学理论与实践;2010年05期
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