目的以一个临床表型为低血磷性佝偻病(hypophosphatemic rickets,HR)的家系为研究对象,通过全外显子组测序寻找该家系的致病变异基因,并分析变异的致病性。方法收集HR家系临床资料,进行生化检测。提取先证者DNA,进行临床全外显子组测序...目的以一个临床表型为低血磷性佝偻病(hypophosphatemic rickets,HR)的家系为研究对象,通过全外显子组测序寻找该家系的致病变异基因,并分析变异的致病性。方法收集HR家系临床资料,进行生化检测。提取先证者DNA,进行临床全外显子组测序,并针对可疑致病变异对家系所有成员进行PCR扩增,Sanger测序验证。预测变异的致病性及对蛋白质空间结构的影响。结果该家系共3代,先证者是一位26岁女性,先证者母亲、先证者及其儿子和女儿为患者,临床表现为O型腿、鸡胸、低磷血症,骨骼X线检查、生化检测、成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)检测结果提示低血磷性佝偻病。临床全外显子组测序发现PHEX(NM_000444)c.2193dupT的插入移码杂合变异,该变异可导致编码第732位的天冬酰胺变异为终止密码子(p.N732*),从而出现了蛋白质截短。先证者的母亲、儿子及女儿PHEX基因均存在该变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)对变异的分类标准,分级为可能致病性变异。经查阅文献及查找人类基因突变数据库,该变异均未被报道或收录。结论本研究发现了一个PHEX新致病变异,为该家系的临床诊断和治疗及遗传咨询提供了实验依据。展开更多
A decade ago, only two hormones, parathyroid hormone and 1,25（OH）2D, were widely recognized to direct-ly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 （FGF23） in 2000 （1）, our ...A decade ago, only two hormones, parathyroid hormone and 1,25（OH）2D, were widely recognized to direct-ly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 （FGF23） in 2000 （1）, our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteo- blasts in the skeleton （2-3）, it modulates kidney handling of phosphate reabsorption and calcitriol produc-tion. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimentalto humans. In this review, we will discuss the vathovhvsiology of FGF23 and hvver-FGF23 related renal vhosvhate wasting disorders （4）.展开更多
X-连锁低磷性佝偻病(X-linked Hypophosphatemic rickets,XLH)是一种罕见的磷代谢失衡的骨矿化障碍性疾病,发病率为(3.9~5.0)/10万[1]。XLH是由与X染色体上的内肽酶同源的磷酸盐调节基因(phosphate regulating gene with homologies to ...X-连锁低磷性佝偻病(X-linked Hypophosphatemic rickets,XLH)是一种罕见的磷代谢失衡的骨矿化障碍性疾病,发病率为(3.9~5.0)/10万[1]。XLH是由与X染色体上的内肽酶同源的磷酸盐调节基因(phosphate regulating gene with homologies to endopeptidases on the X-chromosome,PHEX)突变引起的,为X连锁显性遗传。PHEX基因突变导致血清成纤维细胞生长因子-23(fibroblast growth factor-23,FGF-23)水平升高,使得近端肾小管对磷酸盐的重吸收下降,造成尿磷排出增多、血清磷水平下降[2],从而引起患儿进行性下肢畸形、不成比例身材矮小、牙龈脓肿等。XLH的罕见性与临床表现的多样性往往会延迟该病的诊断和治疗,因此提高临床诊治认识、了解疾病预后至关重要。本文报道一家系先证者及其亲属的病例资料,并通过文献复习对该病的诊治进行梳理。展开更多
文摘目的以一个临床表型为低血磷性佝偻病(hypophosphatemic rickets,HR)的家系为研究对象,通过全外显子组测序寻找该家系的致病变异基因,并分析变异的致病性。方法收集HR家系临床资料,进行生化检测。提取先证者DNA,进行临床全外显子组测序,并针对可疑致病变异对家系所有成员进行PCR扩增,Sanger测序验证。预测变异的致病性及对蛋白质空间结构的影响。结果该家系共3代,先证者是一位26岁女性,先证者母亲、先证者及其儿子和女儿为患者,临床表现为O型腿、鸡胸、低磷血症,骨骼X线检查、生化检测、成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)检测结果提示低血磷性佝偻病。临床全外显子组测序发现PHEX(NM_000444)c.2193dupT的插入移码杂合变异,该变异可导致编码第732位的天冬酰胺变异为终止密码子(p.N732*),从而出现了蛋白质截短。先证者的母亲、儿子及女儿PHEX基因均存在该变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)对变异的分类标准,分级为可能致病性变异。经查阅文献及查找人类基因突变数据库,该变异均未被报道或收录。结论本研究发现了一个PHEX新致病变异,为该家系的临床诊断和治疗及遗传咨询提供了实验依据。
基金supported by the National Natural Science Foundation of China (No.81070687 and 8117-0805)National Science and Technology Major Projects for"Major New Drugs Innovation and Development"(Grant No.2008ZX09312-016)Beijing Natural Science Foundation(No.7121012)
文摘A decade ago, only two hormones, parathyroid hormone and 1,25（OH）2D, were widely recognized to direct-ly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 （FGF23） in 2000 （1）, our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteo- blasts in the skeleton （2-3）, it modulates kidney handling of phosphate reabsorption and calcitriol produc-tion. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimentalto humans. In this review, we will discuss the vathovhvsiology of FGF23 and hvver-FGF23 related renal vhosvhate wasting disorders （4）.
文摘X-连锁低磷性佝偻病(X-linked Hypophosphatemic rickets,XLH)是一种罕见的磷代谢失衡的骨矿化障碍性疾病,发病率为(3.9~5.0)/10万[1]。XLH是由与X染色体上的内肽酶同源的磷酸盐调节基因(phosphate regulating gene with homologies to endopeptidases on the X-chromosome,PHEX)突变引起的,为X连锁显性遗传。PHEX基因突变导致血清成纤维细胞生长因子-23(fibroblast growth factor-23,FGF-23)水平升高,使得近端肾小管对磷酸盐的重吸收下降,造成尿磷排出增多、血清磷水平下降[2],从而引起患儿进行性下肢畸形、不成比例身材矮小、牙龈脓肿等。XLH的罕见性与临床表现的多样性往往会延迟该病的诊断和治疗,因此提高临床诊治认识、了解疾病预后至关重要。本文报道一家系先证者及其亲属的病例资料,并通过文献复习对该病的诊治进行梳理。
