低血磷性佝偻病/骨软化的遗传学研究进行性骨化性纤维组织结构不良的基因突变检测
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摘要
第一部分低血磷性佝偻病/骨软化的遗传学研究
背景
低血磷性佝偻病/骨软化症(hypophosphatemic rickets/osteomalacia，以往称为维生素D-抵抗的软骨病/佝偻病)是一组并不罕见的致畸/致残性疾病,如果发生在儿童,会出现方颅、鸡胸、肋骨串珠、下肢弯曲畸形,表现为“O”型或“X”型腿以及生长发育迟缓等；如果发生在成人,则会表现为乏力、体形改变、身材变矮、多发骨折、骨痛甚至致残。其中最常见的类型,X连锁显性遗传的低血磷性佝偻病(XLH)的致病基因是位于X染色体的PHEX基因,迄今在世界各人种已报道有260个不同类型的PHEX基因突变,但有关XLH的表型和基因型间的关系尚存在争议,发病机制也未完全阐明。对于临床上有典型XLH表现的患者进行PHEX基因突变的检测在产前诊断和预后方面有非常重要的意义。而对于PHEX蛋白功能的研究可进一步揭示其对肾脏磷的转运,骨骼矿化的影响,探求PHEX蛋白与FGF23、MEPE、DMP1和ASARM等调磷因子间的相互作用方式,为从分子水平改善XLH低磷血症的药物研究提供理论依据。
目的
1.筛查和检测低血磷性佝偻病/骨软化患者的致病基因
2.分析和总结XLH患者的临床特点
3.分析XLH患者的表型及基因型间的关系
4.研究PHEX基因突变的蛋白质的功能
对象和方法
1.研究对象：北京协和医院收治的128例低血磷性佝偻病/骨软化患者
2.研究方法：
1)在签署知情同意书后,采集受试者的血液和尿液标本,提取DNA和进行生化指标的检测；同时提取50例健康志愿者的全血DNA标本作为研究对照
2)基因突变分析：针对检测基因(PHEX、FGF23、DMP1、SLC34A3)设计PCR扩增引物,对所有受试者的DNA进行PCR扩增,扩增产物进行琼脂糖凝胶纯化,使用测序仪直接测序,测序结果与参考序列比对后寻找变异点；所有突变点均在50例健康志愿者中进行验证
3) PHEX功能研究：对PHEX蛋白的野生型表达质粒pCDNA3/RSV/PHEX和PCMV6-Entry/PHEX,利用定点诱变的方法构建突变型的质粒,突变点为在128例低血磷性佝偻病/骨软化患者中发现的c.254G>C、c.1216 T>A和c.1843A>C三个未经报导的错义突变。使用脂质体法转染HEK293细胞,通过RT-PCR检测目的基因的mRNA表达,通过Western-Blot对蛋白的表达进行检测；底物反应所使用的物质为重组的人FGF23纯品和人工合成的ASARM多肽,检测方法包括ELISA和液相色谱-串联质谱。
4)统计学分析：表型和基因型关系研究采用以家系为单位的Fisher's精确检验(双向)。
结果
1.对128例低血磷性佝偻病患者进行了致病基因突变的检测,包括PHEX、FGF23、DMP1和SLC34A3基因。在其中33例患者发现了PHEX基因的突变,一例患者发现了FGF23基因的突变,其余患者尚未发现以上各基因的突变。
2.对33例确诊为XLH的患者(其中包括8个家系型XLH患者)进行了临床资料的总结和分析。患者的就诊年龄从10个月到58岁,发病平均年龄为18个月,低磷血症、骨骼畸形和牙齿疾患是最常见的临床表现。有24例患者(占72.7%)存在下肢膝内翻畸形,有18例患者存在牙齿疾患(占54.5%)。临床生化检查除了血磷低,有29例患者(占87.9%)有血ALP增高的表现。5例患者在长时间口服中性磷和活性维生素D治疗后,出现了肾脏钙化或钙质沉积,具体原因尚不清楚。
3.本研究发现的33个PHEX基因突变中,有20个是国内外尚未报导的突变,有9个突变位于保守序列区域。突变类型有多种,包括7个错义突变(c.565 C>Tc.254G>C、c.1735G>A、c.10G>C、c.1216 T>A、c.1843A>C、c.1601 C>T),7个无义突变(c.58C＞T、c.670C＞T、c.1103 G>A、c.2140C＞T、c.365A>C、c.28G>T和c.2104 C>T),5个剪切位点的突变(c.664-1G>C、c.1174-2 A>G、c.1645+2 G>A、c.933+1G＞A、c.1645+6 T>C),3个缺失突变(c.464_465del C、c.1480_1487delCTGTAAG、c.997_999 del T),还有7个小片段插入突变(c.2006_2007insCTTGA、c.2063_2064ins GTTA、c.2029_2030ins GGCATCA、c.1919 1920 ins G、c.1909 1910 ins GGTCAAGGGGA、c.2062 2063 Ins GTT)。
4.在对33例XLH患者的表型和基因型的关系的分析中,本研究选取了发病年龄和牙齿疾病作为两个最主要的表型,基因型则分为氨基酸的截短和非截短突变,649位氨基酸的5’端和3’端的突变两类。以家庭为单位进行统计学分析后发现,不管是发病年龄还是牙齿疾病,与突变类型间都没有发现显著的统计学关联。
5.对一个常染色体显性遗传低血磷性佝偻病(ADHR)的家系进行了临床特点的分析和基因突变的检测。先证者为女性,除了严重的低磷血症外,还具有发病晚、病情隐匿、骨骼畸形不明显等特点。家系的4名成员的血清i-FGF23均未出现显著的升高。此外,先证者、其弟弟和母亲存在FGF23基因c.527G>A (p.R176Q)的突变,但除先证者外均无低磷血症和佝偻病的临床表现。
6.研究选取了3个未报导的错义突变点c.254G>C (p.C85S)、c.1216 T>A(p.C406S)和c.1843A>C (p.T615P)进行了PHEX基因功能的研究。研究成功构建了PHEX基因的突变型的两种表达质粒PCMV6/PHEX和pCDNA3/RSV/ PHEX,并成功转染了HEK293细胞进行PHEX野生型和突变型蛋白的表达(RNA和蛋白水平均得到验证)。
结论
本研究对128例临床诊断低血磷性佝偻病/骨软化的患者进行了遗传学的筛查和检测,涉及的基因包括PHEX、FGF23、SLC34A3和DMP1,在33例患者中发现了PHEX基因的突变,其中包括20个尚未见报导的突变点,在1例患者发现了FGF23基因的突变。在对33例XLH患者的表型和基因型的关系的分析中,发病年龄和牙齿疾病与突变类型间未发现显著的统计学关联。在选取了3个未报导的错义突变点c.254G>C (p.C85S)、c.1216 T>A (p.C406S)和c.1843A>C (p.T615P)进行了PHEX基因功能的研究中,成功构建了PHEX基因的突变型的两种表达质粒PCMV6/PHEX和pCDNA3/RSV/PHEX,并成功转染了HEK293细胞进行PHEX野生型和突变型蛋白的表达(RNA和蛋白水平均得到验证)。
第二部分进行性骨化性纤维组织结构不良的基因突变检测
背景
进行性骨化性纤维组织结构不良(FOP)是一种少见的先天性结缔组织病,临床上以先天性大脚趾畸形,再发的软组织疼痛和肿胀并出现异位骨化为特征。最近的研究发现与该病相关的致病基因是ACVR1,该基因编码骨形态发生蛋白(BMP)的Ⅰ型受体蛋白。
目的
对两例诊断FOP的中国患者进行临床资料的总结和ACVR1基因的突变检测,以求发现FOP的临床特点和遗传学改变。
研究对象和方法
1.研究对象：本研究的对象为2006年-2008年间就诊于北京协和医院内分泌科的两例诊断为进行性骨化性纤维组织结构不良(FOP)的患者及其一级亲属。
2.临床资料：患者1,18岁男性,13岁时主因“发现骨性结节10年”就诊,3岁时后颈部出现无痛性骨性结节,呈渐进性,逐渐发展到髋部和背部,平时外伤后受伤部位会逐渐出现骨性结节,足部有大脚趾短畸形,走路步态僵硬,张口受限,颈部和腰部活动中度受限；患者2,16岁男性,主因“多关节痛13年伴关节渐进性强直”就诊,3岁时开始出现皮下骨性硬结,由头部发展到背部、髋部及大腿,并出现腰背部疼痛,疼痛不剧烈,关节活动逐渐受限发展为强直状态,在外伤后受伤部位会逐渐形成骨性结节,脊柱及双髋关节活动严重受限,抬腿受限。足部有大脚趾短畸形,拇外翻畸形。两例患者家族中均无类似疾病患者。
3. ACVR1基因的突变检测：签署知情同意书后,采集两例患者及其家系成员的外周血。基因组DNA用全血DNA提取试剂盒从外周血白细胞中抽提。ACVR1基因的编码序列和内含子/外显子交接区片断采用PCR的方法扩增。扩增产物直接纯化和测序。突变分析是将测得序列与基因组参考序列比对而得。
4.采用限制性内切酶酶切的方法验证突变。对患者的父母以及50例健康志愿者(对照)的DNA行PCR所得产物使用Cac8Ⅰ酶切后行琼脂糖凝胶电泳验证。
结果
对于两例FOP患者ACVR1的基因检测,发现一个杂合的错义突变c.617G>A(p,R206H)。在患者家庭里这是个新发突变。在中国患者中这个突变是再发的。
结论
通过对两个FOP家系进行的致病基因ACVR1的突变检测,发现了2例先证者都存在一个位于4号外显子的杂合突变c.617G＞A (p.R206H),该突变为存在于各种族FOP患者中的一个热点突变。
Part I Genetic analysis of patients with hypophosphatemic rickets/Osteomalacia
Introduction
X-linked dominant hypophosphatemia, 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 as PHEX (formerly PEX) to depict a phosphate regulating gene with homology to endopeptidases on the X chromosome. Some previous studies of genotype-phenotype relationship analysis showed that there was no correlation between severity of disease and type and location of PHEX mutation. However, the conclusion is controversial. Moreover, functional study about PHEX gene will reveal the precise mechanism of this kind of disease, which provides more advices of follow-up and treatment.
Objective
1. To analyze the clinical manifestations of the patients diagnosed with XLH.
2. To detect the disease-causing gene mutations in total 128 patients with hypophosphatemic rickets/osteomalacia in Department of Endocrinology of PUMCH.
3. To find the phenotype-genotype association of the patients with XLH.
4. To find the functional change of PHEX protein via in vitro study.
Subjects and Methods
Subjects:128 patients with hypophosphatemic rickets/osteomalacia in Department of Endocrinology of PUMCH.
Methods
1. All the clinical information was analyzed.
2. After obtaining appropriate consent, blood samples were taken from the patients and their family members. Genomic DNA was extracted from peripheral blood of the patient and 50 ethnically matched controls.
3. PHEX, FGF23, DMP1 and SLC34A3 gene fragments covering the entire coding region and intron/exon boundaries were amplified by PCR. The amplified products were directly purified and sequenced. Mutations were identified by comparing the sequences against the DNA of reference gene sequences. All the mutations were confirmed in the 50 ethnically matched controls.
4. We constructed the PHEX expression vectors (with or without mutation) and transfected the vectors into HEK293 cells. After 36 hours expression, we extracted the total RNA from cells and performed RT-PCR to detect PHEX mRNA. We performed Western-Blot to detect the expressed PHEX protein. The substrates of PHEX we used in the proteolysis study include human recombined i-FGF23 and ASARM polypeptide and we used ELISA kit and LC-MS/MS to detect the product.
5. Statistical analysis:we performed Fisher's exact test in the phenotype-genotype association study.
Results
1. We performed gene mutation analysis in 128 patients with hypophosphatemic rickets/osteomalacia and found 33 PHEX gene mutations and one FGF23 gene mutation.
2. After summarizing all the clinical information from 33 patients with XLH (including 8 familial cases), we found that some characteristic features such as early onset of disease (mean age of onset=18 months), severe hypophosphatemia, skeletal deformities and dental problems are most common. Many patients had increased serum ALP concentration. Several patients were found to have nephrolithiasis after long-time treatment of neutral phosphorus and active vitamin D. The reason is not clear.
3. PHEX gene analysis of the 33 Chinese pedigrees revealed 29 different mutations, including 20 novel mutations and nine mutations that have been previously described in the literature or entered in PHEXdb as personal submission. It consists of 7 missense (24.1%),7 nonsense (24.1%),3 deletions (10.3%),7 insertions (24.1%) and 5 splice site mutations (17.2%). The 29 mutations are scattered widely throughout the whole gene and 9 of them (31%) located in conserved domains. Of the 20 novel mutations,3 were missense,3 were nonsense,3 were deletions,6 were insertions and 5 were splice site mutations. And 6 of them (30%) were found in familial cases.
4. The phenotype-genotype association study showed no significant relationship between the age of onset or dental problems and gene mutations.
5. We reported a family of Chinese ethnic with ADHR. The diagnosis was confirmed based on the clinical and molecular genetic analysis. A single heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene was detected in three of the family members including the proband, her brother and their mother.
6. A functional study was performed to elucidate the effect of three missense mutations including c.254G>C (p.C85S),c.1216 T>A (p.C406S) and c.1843A>C (p.T615P) on proteolysis of PHEX protein. We successfully established the HEK293 expression cell culture model, and the expression of wild type and the mutant PHEX gene were proved similar. More studies are necessary for functional analysis and the mechanism remains to elucidate.
Conclusion
In the present study we concluded the clinical manifestations and analyzed the PHEX gene mutations in 33 Chinese pedigrees with XLH, including familial and sporadic cases. The phenotype-genotype association study showed no significant relationship between the age of onset or dental problems and gene mutations. We reported a family of Chinese ethnic with ADHR carrying a heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene. A functional study was performed to elucidate the effect of three missense mutations including c.254G>C (p.C85S),c.1216 T>A (p.C406S) and c.1843A>C (p.T615P) on proteolysis of PHEX protein. We successfully established wildtype and mutanted expression plasmid. However, more investigations should be performed to elucidate the precise mechanism of how PHEX involved in the pathology of those phosphate-wasting diseases.
Part II Mutation analysis of ACVR1 gene in two Chinese patients with fibrodysplasia ossificans progressiva
Introduction
Fibrodysplasia ossificans progressiva (FOP, OMIM 135100) is a rare heritable disorder of connective tissue characterized by congenital malformations of the great toes and recurrent episodes of painful soft-tissue swelling, leading to heterotopic ossifications. First described in 1692, FOP has been documented in all races. In 1982, the incidence of FOP was estimated to be approximately 1:1640000. Autosomal dominant transmission with variable expressivity has been established. Recently, Shore et al. successfully mapped FOP to chromosome 2q23-24 by genome-wide linkage analysis. They identified an identical heterozygous mutation (c.617G> A; p.R206H) in the glycine-serine (GS) activation domain of ACVR1 (OMIM 102576; also known as Alk2 or ActRIA), a BMP type I receptor, in all affected individuals examined. The c.617G> A mutation in the ACVR1 gene is also recurrent in Asian patients with FOP. In this study, we investigated the ACVR1 gene mutation in two Chinese patients diagnosed as FOP.
Objective
Our study is amied to investigate the ACVR1 gene mutation in two Chinese patients diagnosed with FOP.
Subjects and methods
1. Subjects:We observed two Chinese patients suffered from progressive pain and ankylosis of major joints with congenital bilateral hallus valgo deformation, neck stiffness and several post-traumatic ossified lesions on the head and dorsum. Both of them were diagnosed with FOP. Patient 1 is an 18 year old boy, suffered from multiple progressive painful swellings in synovial joints including hips and knee joints over 13 years. He also had limitation of the spinal movement and progressive ankylosis of lumbar spine. He was found to have bilateral hallus valgo deformation, neck stiffness and several post-traumatic ossified lesions on the head (temporal), dorsum and left hip since he was 3 years old. Patient 2 was a 16 year old boy who suffered from multiple progressive painful swellings in synovial joints, including hips and knee joints, over 13 years. From the age of 3 years, the patient had several post-traumatic ossified lesions on the head, dorsum and right hip. The patient had scoliosis and cervical stiffness since the age of 4. He had bilateral hallus valgus malformation. The family history of both patients was negative.
2. After obtaining appropriate consent, blood samples were taken from the patient2, the parents of the two families and 50 ethnically-matched unrelated controls. Genomic DNA was isolated from extracted from peripheral blood of the patient and his parents by standard Phenol-chloroform extraction procedure. The ACVR1 gene fragments covering the entire coding region and intron/exon boundaries were amplified by PCR. The amplified products were directly purified and sequenced. Mutations were identified by comparing the sequences against the DNA of the ACVR1 gene.
3. Mutation confirmed by restriction enzyme digestion. Samples from parents of the patient's family and 50 healthy controls were amplified by PCR. The production were digested by Cac8I and the digested samples were underwent electrophoreses.
Results
We detected a heterozygote missense mutation 617G>A (R206H) in the ACVR1 gene in two Chinese patients with FOP. The 617G>A mutation was de novo in their families. It was a recurrent mutation of ACVR1 gene in two Chinese patients.
Conclusions
We investigated the ACVR1 gene mutation in two Chinese patients diagnosed with FOP. As we expected, we found the 617G> A (R206H) mutation in two Chinese FOP patients. It was a recurrent mutation of ACVR1 gene in Chinese patients.
背景
低血磷性佝偻病/骨软化症(hypophosphatemic rickets/osteomalacia，以往称为维生素D-抵抗的软骨病/佝偻病)是一组并不罕见的致畸/致残性疾病,如果发生在儿童,会出现方颅、鸡胸、肋骨串珠、下肢弯曲畸形,表现为“O”型或“X”型腿以及生长发育迟缓等；如果发生在成人,则会表现为乏力、体形改变、身材变矮、多发骨折、骨痛甚至致残。其中最常见的类型,X连锁显性遗传的低血磷性佝偻病(XLH)的致病基因是位于X染色体的PHEX基因,迄今在世界各人种已报道有260个不同类型的PHEX基因突变,但有关XLH的表型和基因型间的关系尚存在争议,发病机制也未完全阐明。对于临床上有典型XLH表现的患者进行PHEX基因突变的检测在产前诊断和预后方面有非常重要的意义。而对于PHEX蛋白功能的研究可进一步揭示其对肾脏磷的转运,骨骼矿化的影响,探求PHEX蛋白与FGF23、MEPE、DMP1和ASARM等调磷因子间的相互作用方式,为从分子水平改善XLH低磷血症的药物研究提供理论依据。
目的
1.筛查和检测低血磷性佝偻病/骨软化患者的致病基因
2.分析和总结XLH患者的临床特点
3.分析XLH患者的表型及基因型间的关系
4.研究PHEX基因突变的蛋白质的功能
对象和方法
1.研究对象：北京协和医院收治的128例低血磷性佝偻病/骨软化患者
2.研究方法：
1)在签署知情同意书后,采集受试者的血液和尿液标本,提取DNA和进行生化指标的检测；同时提取50例健康志愿者的全血DNA标本作为研究对照
2)基因突变分析：针对检测基因(PHEX、FGF23、DMP1、SLC34A3)设计PCR扩增引物,对所有受试者的DNA进行PCR扩增,扩增产物进行琼脂糖凝胶纯化,使用测序仪直接测序,测序结果与参考序列比对后寻找变异点；所有突变点均在50例健康志愿者中进行验证
3) PHEX功能研究：对PHEX蛋白的野生型表达质粒pCDNA3/RSV/PHEX和PCMV6-Entry/PHEX,利用定点诱变的方法构建突变型的质粒,突变点为在128例低血磷性佝偻病/骨软化患者中发现的c.254G>C、c.1216 T>A和c.1843A>C三个未经报导的错义突变。使用脂质体法转染HEK293细胞,通过RT-PCR检测目的基因的mRNA表达,通过Western-Blot对蛋白的表达进行检测；底物反应所使用的物质为重组的人FGF23纯品和人工合成的ASARM多肽,检测方法包括ELISA和液相色谱-串联质谱。
4)统计学分析：表型和基因型关系研究采用以家系为单位的Fisher's精确检验(双向)。
结果
1.对128例低血磷性佝偻病患者进行了致病基因突变的检测,包括PHEX、FGF23、DMP1和SLC34A3基因。在其中33例患者发现了PHEX基因的突变,一例患者发现了FGF23基因的突变,其余患者尚未发现以上各基因的突变。
2.对33例确诊为XLH的患者(其中包括8个家系型XLH患者)进行了临床资料的总结和分析。患者的就诊年龄从10个月到58岁,发病平均年龄为18个月,低磷血症、骨骼畸形和牙齿疾患是最常见的临床表现。有24例患者(占72.7%)存在下肢膝内翻畸形,有18例患者存在牙齿疾患(占54.5%)。临床生化检查除了血磷低,有29例患者(占87.9%)有血ALP增高的表现。5例患者在长时间口服中性磷和活性维生素D治疗后,出现了肾脏钙化或钙质沉积,具体原因尚不清楚。
3.本研究发现的33个PHEX基因突变中,有20个是国内外尚未报导的突变,有9个突变位于保守序列区域。突变类型有多种,包括7个错义突变(c.565 C>Tc.254G>C、c.1735G>A、c.10G>C、c.1216 T>A、c.1843A>C、c.1601 C>T),7个无义突变(c.58C＞T、c.670C＞T、c.1103 G>A、c.2140C＞T、c.365A>C、c.28G>T和c.2104 C>T),5个剪切位点的突变(c.664-1G>C、c.1174-2 A>G、c.1645+2 G>A、c.933+1G＞A、c.1645+6 T>C),3个缺失突变(c.464_465del C、c.1480_1487delCTGTAAG、c.997_999 del T),还有7个小片段插入突变(c.2006_2007insCTTGA、c.2063_2064ins GTTA、c.2029_2030ins GGCATCA、c.1919 1920 ins G、c.1909 1910 ins GGTCAAGGGGA、c.2062 2063 Ins GTT)。
4.在对33例XLH患者的表型和基因型的关系的分析中,本研究选取了发病年龄和牙齿疾病作为两个最主要的表型,基因型则分为氨基酸的截短和非截短突变,649位氨基酸的5’端和3’端的突变两类。以家庭为单位进行统计学分析后发现,不管是发病年龄还是牙齿疾病,与突变类型间都没有发现显著的统计学关联。
5.对一个常染色体显性遗传低血磷性佝偻病(ADHR)的家系进行了临床特点的分析和基因突变的检测。先证者为女性,除了严重的低磷血症外,还具有发病晚、病情隐匿、骨骼畸形不明显等特点。家系的4名成员的血清i-FGF23均未出现显著的升高。此外,先证者、其弟弟和母亲存在FGF23基因c.527G>A (p.R176Q)的突变,但除先证者外均无低磷血症和佝偻病的临床表现。
6.研究选取了3个未报导的错义突变点c.254G>C (p.C85S)、c.1216 T>A(p.C406S)和c.1843A>C (p.T615P)进行了PHEX基因功能的研究。研究成功构建了PHEX基因的突变型的两种表达质粒PCMV6/PHEX和pCDNA3/RSV/ PHEX,并成功转染了HEK293细胞进行PHEX野生型和突变型蛋白的表达(RNA和蛋白水平均得到验证)。
结论
本研究对128例临床诊断低血磷性佝偻病/骨软化的患者进行了遗传学的筛查和检测,涉及的基因包括PHEX、FGF23、SLC34A3和DMP1,在33例患者中发现了PHEX基因的突变,其中包括20个尚未见报导的突变点,在1例患者发现了FGF23基因的突变。在对33例XLH患者的表型和基因型的关系的分析中,发病年龄和牙齿疾病与突变类型间未发现显著的统计学关联。在选取了3个未报导的错义突变点c.254G>C (p.C85S)、c.1216 T>A (p.C406S)和c.1843A>C (p.T615P)进行了PHEX基因功能的研究中,成功构建了PHEX基因的突变型的两种表达质粒PCMV6/PHEX和pCDNA3/RSV/PHEX,并成功转染了HEK293细胞进行PHEX野生型和突变型蛋白的表达(RNA和蛋白水平均得到验证)。
第二部分进行性骨化性纤维组织结构不良的基因突变检测
背景
进行性骨化性纤维组织结构不良(FOP)是一种少见的先天性结缔组织病,临床上以先天性大脚趾畸形,再发的软组织疼痛和肿胀并出现异位骨化为特征。最近的研究发现与该病相关的致病基因是ACVR1,该基因编码骨形态发生蛋白(BMP)的Ⅰ型受体蛋白。
目的
对两例诊断FOP的中国患者进行临床资料的总结和ACVR1基因的突变检测,以求发现FOP的临床特点和遗传学改变。
研究对象和方法
1.研究对象：本研究的对象为2006年-2008年间就诊于北京协和医院内分泌科的两例诊断为进行性骨化性纤维组织结构不良(FOP)的患者及其一级亲属。
2.临床资料：患者1,18岁男性,13岁时主因“发现骨性结节10年”就诊,3岁时后颈部出现无痛性骨性结节,呈渐进性,逐渐发展到髋部和背部,平时外伤后受伤部位会逐渐出现骨性结节,足部有大脚趾短畸形,走路步态僵硬,张口受限,颈部和腰部活动中度受限；患者2,16岁男性,主因“多关节痛13年伴关节渐进性强直”就诊,3岁时开始出现皮下骨性硬结,由头部发展到背部、髋部及大腿,并出现腰背部疼痛,疼痛不剧烈,关节活动逐渐受限发展为强直状态,在外伤后受伤部位会逐渐形成骨性结节,脊柱及双髋关节活动严重受限,抬腿受限。足部有大脚趾短畸形,拇外翻畸形。两例患者家族中均无类似疾病患者。
3. ACVR1基因的突变检测：签署知情同意书后,采集两例患者及其家系成员的外周血。基因组DNA用全血DNA提取试剂盒从外周血白细胞中抽提。ACVR1基因的编码序列和内含子/外显子交接区片断采用PCR的方法扩增。扩增产物直接纯化和测序。突变分析是将测得序列与基因组参考序列比对而得。
4.采用限制性内切酶酶切的方法验证突变。对患者的父母以及50例健康志愿者(对照)的DNA行PCR所得产物使用Cac8Ⅰ酶切后行琼脂糖凝胶电泳验证。
结果
对于两例FOP患者ACVR1的基因检测,发现一个杂合的错义突变c.617G>A(p,R206H)。在患者家庭里这是个新发突变。在中国患者中这个突变是再发的。
结论
通过对两个FOP家系进行的致病基因ACVR1的突变检测,发现了2例先证者都存在一个位于4号外显子的杂合突变c.617G＞A (p.R206H),该突变为存在于各种族FOP患者中的一个热点突变。
Part I Genetic analysis of patients with hypophosphatemic rickets/Osteomalacia
Introduction
X-linked dominant hypophosphatemia, 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 as PHEX (formerly PEX) to depict a phosphate regulating gene with homology to endopeptidases on the X chromosome. Some previous studies of genotype-phenotype relationship analysis showed that there was no correlation between severity of disease and type and location of PHEX mutation. However, the conclusion is controversial. Moreover, functional study about PHEX gene will reveal the precise mechanism of this kind of disease, which provides more advices of follow-up and treatment.
Objective
1. To analyze the clinical manifestations of the patients diagnosed with XLH.
2. To detect the disease-causing gene mutations in total 128 patients with hypophosphatemic rickets/osteomalacia in Department of Endocrinology of PUMCH.
3. To find the phenotype-genotype association of the patients with XLH.
4. To find the functional change of PHEX protein via in vitro study.
Subjects and Methods
Subjects:128 patients with hypophosphatemic rickets/osteomalacia in Department of Endocrinology of PUMCH.
Methods
1. All the clinical information was analyzed.
2. After obtaining appropriate consent, blood samples were taken from the patients and their family members. Genomic DNA was extracted from peripheral blood of the patient and 50 ethnically matched controls.
3. PHEX, FGF23, DMP1 and SLC34A3 gene fragments covering the entire coding region and intron/exon boundaries were amplified by PCR. The amplified products were directly purified and sequenced. Mutations were identified by comparing the sequences against the DNA of reference gene sequences. All the mutations were confirmed in the 50 ethnically matched controls.
4. We constructed the PHEX expression vectors (with or without mutation) and transfected the vectors into HEK293 cells. After 36 hours expression, we extracted the total RNA from cells and performed RT-PCR to detect PHEX mRNA. We performed Western-Blot to detect the expressed PHEX protein. The substrates of PHEX we used in the proteolysis study include human recombined i-FGF23 and ASARM polypeptide and we used ELISA kit and LC-MS/MS to detect the product.
5. Statistical analysis:we performed Fisher's exact test in the phenotype-genotype association study.
Results
1. We performed gene mutation analysis in 128 patients with hypophosphatemic rickets/osteomalacia and found 33 PHEX gene mutations and one FGF23 gene mutation.
2. After summarizing all the clinical information from 33 patients with XLH (including 8 familial cases), we found that some characteristic features such as early onset of disease (mean age of onset=18 months), severe hypophosphatemia, skeletal deformities and dental problems are most common. Many patients had increased serum ALP concentration. Several patients were found to have nephrolithiasis after long-time treatment of neutral phosphorus and active vitamin D. The reason is not clear.
3. PHEX gene analysis of the 33 Chinese pedigrees revealed 29 different mutations, including 20 novel mutations and nine mutations that have been previously described in the literature or entered in PHEXdb as personal submission. It consists of 7 missense (24.1%),7 nonsense (24.1%),3 deletions (10.3%),7 insertions (24.1%) and 5 splice site mutations (17.2%). The 29 mutations are scattered widely throughout the whole gene and 9 of them (31%) located in conserved domains. Of the 20 novel mutations,3 were missense,3 were nonsense,3 were deletions,6 were insertions and 5 were splice site mutations. And 6 of them (30%) were found in familial cases.
4. The phenotype-genotype association study showed no significant relationship between the age of onset or dental problems and gene mutations.
5. We reported a family of Chinese ethnic with ADHR. The diagnosis was confirmed based on the clinical and molecular genetic analysis. A single heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene was detected in three of the family members including the proband, her brother and their mother.
6. A functional study was performed to elucidate the effect of three missense mutations including c.254G>C (p.C85S),c.1216 T>A (p.C406S) and c.1843A>C (p.T615P) on proteolysis of PHEX protein. We successfully established the HEK293 expression cell culture model, and the expression of wild type and the mutant PHEX gene were proved similar. More studies are necessary for functional analysis and the mechanism remains to elucidate.
Conclusion
In the present study we concluded the clinical manifestations and analyzed the PHEX gene mutations in 33 Chinese pedigrees with XLH, including familial and sporadic cases. The phenotype-genotype association study showed no significant relationship between the age of onset or dental problems and gene mutations. We reported a family of Chinese ethnic with ADHR carrying a heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene. A functional study was performed to elucidate the effect of three missense mutations including c.254G>C (p.C85S),c.1216 T>A (p.C406S) and c.1843A>C (p.T615P) on proteolysis of PHEX protein. We successfully established wildtype and mutanted expression plasmid. However, more investigations should be performed to elucidate the precise mechanism of how PHEX involved in the pathology of those phosphate-wasting diseases.
Part II Mutation analysis of ACVR1 gene in two Chinese patients with fibrodysplasia ossificans progressiva
Introduction
Fibrodysplasia ossificans progressiva (FOP, OMIM 135100) is a rare heritable disorder of connective tissue characterized by congenital malformations of the great toes and recurrent episodes of painful soft-tissue swelling, leading to heterotopic ossifications. First described in 1692, FOP has been documented in all races. In 1982, the incidence of FOP was estimated to be approximately 1:1640000. Autosomal dominant transmission with variable expressivity has been established. Recently, Shore et al. successfully mapped FOP to chromosome 2q23-24 by genome-wide linkage analysis. They identified an identical heterozygous mutation (c.617G> A; p.R206H) in the glycine-serine (GS) activation domain of ACVR1 (OMIM 102576; also known as Alk2 or ActRIA), a BMP type I receptor, in all affected individuals examined. The c.617G> A mutation in the ACVR1 gene is also recurrent in Asian patients with FOP. In this study, we investigated the ACVR1 gene mutation in two Chinese patients diagnosed as FOP.
Objective
Our study is amied to investigate the ACVR1 gene mutation in two Chinese patients diagnosed with FOP.
Subjects and methods
1. Subjects:We observed two Chinese patients suffered from progressive pain and ankylosis of major joints with congenital bilateral hallus valgo deformation, neck stiffness and several post-traumatic ossified lesions on the head and dorsum. Both of them were diagnosed with FOP. Patient 1 is an 18 year old boy, suffered from multiple progressive painful swellings in synovial joints including hips and knee joints over 13 years. He also had limitation of the spinal movement and progressive ankylosis of lumbar spine. He was found to have bilateral hallus valgo deformation, neck stiffness and several post-traumatic ossified lesions on the head (temporal), dorsum and left hip since he was 3 years old. Patient 2 was a 16 year old boy who suffered from multiple progressive painful swellings in synovial joints, including hips and knee joints, over 13 years. From the age of 3 years, the patient had several post-traumatic ossified lesions on the head, dorsum and right hip. The patient had scoliosis and cervical stiffness since the age of 4. He had bilateral hallus valgus malformation. The family history of both patients was negative.
2. After obtaining appropriate consent, blood samples were taken from the patient2, the parents of the two families and 50 ethnically-matched unrelated controls. Genomic DNA was isolated from extracted from peripheral blood of the patient and his parents by standard Phenol-chloroform extraction procedure. The ACVR1 gene fragments covering the entire coding region and intron/exon boundaries were amplified by PCR. The amplified products were directly purified and sequenced. Mutations were identified by comparing the sequences against the DNA of the ACVR1 gene.
3. Mutation confirmed by restriction enzyme digestion. Samples from parents of the patient's family and 50 healthy controls were amplified by PCR. The production were digested by Cac8I and the digested samples were underwent electrophoreses.
Results
We detected a heterozygote missense mutation 617G>A (R206H) in the ACVR1 gene in two Chinese patients with FOP. The 617G>A mutation was de novo in their families. It was a recurrent mutation of ACVR1 gene in two Chinese patients.
Conclusions
We investigated the ACVR1 gene mutation in two Chinese patients diagnosed with FOP. As we expected, we found the 617G> A (R206H) mutation in two Chinese FOP patients. It was a recurrent mutation of ACVR1 gene in Chinese patients.
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