微纤维元基因突变位点特性与新生儿马凡综合征

马凡综合征(MFS)是一种常染色体显性结缔组织疾病,临床上有许多种症状严重类型的MFS,其中最为严重的就是新生儿马凡综合征.这类病人通常患有严重的主动脉反流及主动脉根部扩张,进而导致严重的心力衰竭和死亡.骨骼症状主要包括蜘蛛指(趾),四肢细长,前胸畸形,关节异常活动.大多数的严重的新生儿MFS的FBN1基因突变都集中于外显子24～32区域内.外显子25编码的区域是一cb-EGF区域.与其比邻的是一TGF-β1-BP.该区域是12个连续cb-EGF区域起始部.新生儿MFS成纤维细胞免疫荧光染色展现了微纤维元聚集减少,微原纤维形态异常.和典型MFS成纤维细胞分泌的微原纤维相比,新生儿MFS成纤维细胞分泌的原纤维比较短小,易短裂、破碎.因此,这个区域蛋白形态功能的变化将影响与原纤维的形成.     

马凡综合征患儿原纤维蛋白-1基因突变筛查的研究

目的 探讨马凡综合征(MFS)患儿原纤维蛋白-1基因(FBN1)的新发突变并分析其基因型与表型的关系,为MFS患儿提供基因诊断依据.方法 选取我院2010年1月-2011年12月收治的8例MFS患儿,行超声心动图、心电图和胸部X线检查,并提取外周血DNA,利用聚合酶链反应-单链构象多态性技术(PCR-SSCP)和DNA测序技术,与FBN1突变数据库及健康儿童FBN1的DNA进行对比,确定突变位点和类型.结果发现1例新发错义突变c.2638G>A和1例新发PTC突变c.IVS30+1A>G,1例已知MFS的错义突变c.3349T>C.结论 PTC突变c.IVS30+1A>G和错义突变c.2638G>A、c.3349T>C可能是MFS的致病原因,应用PCR-SSCP-DNA测序方法 能为儿童MFS基因诊断提供依据.     

马凡综合征患儿原纤维蛋白-1基因突变筛查的研究

目的探讨马凡综合征(MFS)患儿原纤维蛋白-1基因(FBN1)的新发突变并分析其基因型与表型的关系,为MFS患儿提供基因诊断依据。方法选取我院2010年1月—2011年12月收治的8例MFS患儿,行超声心动图、心电图和胸部X线检查,并提取外周血DNA,利用聚合酶链反应-单链构象多态性技术(PCR-SSCP)和DNA测序技术,与FBN1突变数据库及健康儿童FBN1的DNA进行对比,确定突变位点和类型。结果发现1例新发错义突变c.2638G>A和1例新发PTC突变c.IVS30+1A>G,1例已知MFS的错义突变c.3349T>C。结论 PTC突变c.IVS30+1A>G和错义突变c.2638G>A、c.3349T>C可能是MFS的致病原因,应用PCR-SSCP-DNA测序方法能为儿童MFS基因诊断提供依据。     

以眼部症状为主的蝶鞍区及鼻窦肿瘤

本文报道蝶鞍区肿瘤误诊２例，筛窦肿瘤误诊４例。分析误诊原因，强调视野检查对鞍区肿瘤诊断的重要及必要。对单侧眼球突出患者应常规耳鼻喉科检查，排除鼻窦肿瘤的可能性。ＣＴ检查对鼻窦肿瘤的诊断价值是肯定的。     

以咽痛为主要首发症状的马凡综合征1例

<正>患者,男,22岁。主因咽痛2d伴呕吐8次于2015年4月9日19:04首诊我院感染科门诊。患者2d来无明显诱因间断出现咽部紧缩性疼痛,并先后非喷射样呕吐8次,呕吐物均为胃内容物,量不详,无咖啡渣样物质,无发热、头痛、腹泻等,自行用药(具体不详)后症状无明显缓解步行来诊。既往体健。家族史:其母38岁猝死(死因不详)。入院查体:T 36.5℃,P 70次/min,R 22次/min,BP 100/64 mmHg。神志清楚,体型消瘦。双眼斜视。双肺呼吸音清,未闻及干湿性啰音。心率70次/min,心律齐,各瓣膜听诊区未闻及病理性杂音。腹软,无压痛,肠鸣音4次/min。实验室检查:血WBC 12.9×10~9/L,N 0.709,     

3例Wiskott-Aldrich综合征基因突变的特征分析

目的 分析3例Wiskott-Aldrich综合征(WAS)患儿基因型及临床表现,以鉴别诊断要点,拓展诊断方法.方法 收集2018年6月-2020年7月在安徽省儿童医院新生儿科接受治疗的3例WAS患儿资料,采用全外显子组测序(WES)方法检测患儿及其父母WAS基因突变情况,Sanger测序验证突变位点.结果 3例患儿主...     

骨髓增生异常综合征患者FLT3基因及FLT3／ITD基因突变的检测及价值

目的　研究骨髓增生异常综合征 (MDS)患者DNA水平FLT3基因及FLT3 /ITD基因突变情况。方法　采用聚合酶链反应 (PCR)联合单链构象多态性 (SSCP)分析 3 6例MDS患者FLT3基因及FLT3 /ITD基因突变。结果　 3 6例MDS患者中 9例 ( 2 5 %)FLT3基因检测阳性 ,难治性贫血伴原始细胞增多 (RAEB)、慢性粒单细胞白血病和转变中的RAEB(RAEBT)组FLT3基因检测阳性率显著高于难治性贫血 (RA)和环形铁粒幼细胞性难治性贫血 (RAS)组 (P <0 0 2 5 )。FLT3基因检测阳性MDS转化为急性髓性白血病 (AML)时间显著短于FLT3检测阴性患者 (P <0 0 5 )。 3 6例MDS患者中有 2例 ( 5 6%)出现FLT3 /ITD基因突变 ,RAEB及RAEBT各 1例。结论　部分MDS患者可检测出FLT3基因表达和FLT3基因突变 ,FLT3基因及FLT3 /ITD基因突变检测可能有助于MDS的预后判断     

中国人Wolfram综合征WFS1基因的新突变

目的研究一个中国人Wolfram综合征患者家系中的WFS1基因突变情况。方法应用PCR-DNA直接测序对一个Wolfram综合征患者及家系成员的WFS1基因8个外显子及其侧翼内含子进行突变筛查;采用生物信息学方法对突变蛋白的结构与功能进行估测。结果发现外显子8第417位密码子发生缺失突变,即F417del。先证者为突变纯合子,其父母为姑表亲近亲结婚,均为突变杂合子。F417del突变位于跨膜区,失去了一个非极性氨基酸。生物信息学分析提示该突变可引起跨膜区二级结构改变并使突变蛋白疏水性下降。结论本研究发现的F417del突变是一个尚未报道过的Wolfram综合征新突变。     

Hallervorden-Spatz综合征患者一例的临床特征及泛酸激酶2基因突变检测

目的 研究中国Hallervorden-Spatz综合征患者的临床特征并对患者以及家系成员进行泛酸激酶2(PANK2)基因的突变检测.方法 对1例Hallervorden-Spatz综合征患者的临床特征进行分析,应用聚合酶链反应(PCR)、DNA直接测序技术检测患者和其父母及50名健康人PANK2基因序列.结果 患者主要临床表现为进行性加重的四肢不自主运动和构音不清,头部MRI T_2加权和FLAIR成像表现双侧苍白球对称性低信号,在低信号区的前内侧出现高信号,即"虎眼征";检测出PANK2基因一个新的复合杂合突变:位于第1外显子115位的G→T和第二外显子803位的A→G导致所编码的氨基酸发生改变(分别为E39X和D268G).父亲为G115T杂合突变,母亲为A803G杂合突变.结论 中国Hallervorden-Spatz综合征患者存在PANK2基因突变,PANK2基因A803G突变可能为中国大陆Hallervorden-Spatz综合征患者的突变热点.     

以低颅压性头痛为首发症状的马凡综合征1例报告

1临床资料患者,女,26岁,体育教师。因头痛1年,加重5天,于2001年11月3日入院。病人于1年前反复出现运动后前额部胀痛,立位时明显,平卧位减轻,极易疲劳,无心慌、恶心、呕吐。入院前5天无明显诱因症状加重,平卧位亦不能缓解。曾有1次一过性晕厥,未治疗。否认家族中有类似患者。查体:BP113/75mmHg,体型瘦长,身高181cm,体重60kg,蜘蛛指(趾)。心尖搏动于左锁骨中线第5肋间隙,可触及举样搏动,心界不大。胸骨左缘3～4肋间及右缘2～3肋间可闻及2～3级吹风样收缩期杂音及叹气样舒张期杂音。神经系统查体未见异常。辅助检查:双手X线片:掌骨指数8.9(正…     

中国北方一马凡氏综合征家系致病基因突变研究

目的研究确定我国北方一马凡氏综合征(MFS)家系致病基因突变位点。方法对马凡氏综合征一家系进行临床研究和系谱分析。采集家系中3例患者和3例健康成员的静脉血,提取基因组DNA。应用聚合酶链反应(PCR)扩增马凡氏综合征致病基因原纤维蛋白1(FBN1)基因外显子及外显子-内含子接头处,直接测序确定致病的基因突变。结果马凡氏综合征患者的FBN1基因外显子6发生了错义突变,cDNA 640位的鸟嘌呤被腺嘌呤取代(G640A);对应的甘氨酸改变为丝氨酸。突变后EagⅠ内切酶位点消失。该突变在家系中表现为与疾病共分离。结论 FBN1基因突变G640A是该马凡氏综合征家系的致病基因突变。     

FBN1 mutation in Chinese patients with Marfan syndrome and its gene diagnosis using haplotype linkage analysis

Objectives To analyze the FBN1 mutations in Chinese patients with Marfan syndrome (MFS) and to make a genetic diagnosis based on haplotype linkage analysis for MFS.Methods Nine MFS families (17 patients) were analyzed with single strand conformation polymorphism (SSCP) and sequencing. Four primers were designed for the flanking sequences of FBN1 gene and used for haplotype-segregation analysis of MFS (B).Results SSCP band alteration was detected in the PCR products for exon 25 in MFS(A) Ⅱ : 1.Direct sequencing revealed a small 13 bp deletion; the deleted sequence is gccTcTgcaccca at bases 3243 -3456 of the cDNA in exon 25. This mutation was novel. MFS(B) families were analyzed using the haplotype linkage technique. The data suggested that MFS(B) families were linked to the FBN1 gene. The proband‘ s daughter was an asymptomatic patient.Conclusion The combination of mutation detection and chromosome haplotype analysis can provide better evidence for a genetic diagnosis of MFS.     

Identification of a novel lethal fibrillin-1 gene mutation in a Chinese Marfan family and correlation of 3’ fibrillin-1 gene mutations with phenotype

Background Mutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome （MFS）. This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneu rysms/dissection. Methods Two patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed. Results We found a novel mutation （c.8547T〉G, p.Tyr2849X） in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3＇ end of fibrillin-1 gene （exons 64 and 65）, we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death. Conclusions These results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3＇ end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.     

Marfan综合征FBN1基因新的剪接位点的置换突变

目的 对Marfan综合征(MFS)患者的原纤维蛋白-1基因(FBN1)进行突变筛查,探讨MFS患者新的FBN1突变.方法 应用聚合酶链反应(PCR)和变性高效液相色谱法(DHPLC)对1例MFS患者FBN1的65个外显子进行突变筛查,对DHPLC图形异常的PCR扩增片段用DNA测序鉴定突变位点及性质.用限制性片段长度多态性分析法(RFLP)进一步证实突变.结果 发现1种新的FBN1剪接位点的置换突变(Intron29 4A＞T).结论 FBN1的Intron29 4A＞T可能为该MFS患者的发病原因.     

Clinical presentation and surgical treatment of scoliosis in Marfan syndrome

Marfansyndrome(MFS)asanautosomaldominantconnectivetissuediseaseischaracterizedbyocular,cardiovascular,and skeletaldeformitiesincludingscoliosis.1,2Agroup of12patientswithMarfansyndromeassociatedwith scoliosisweresurgicallytreatedatourhospitalfrom January1990toJanuary2004.CLINICALDATA Patients AccordingtoDePaepe’sdiagnosticcriteria,112patientswerediagnosedashavingMarfansyndrome associatedwithscoliosis.Ofthesepatients,2were maleand10female,agedonaverage13.2years(9-16years)uponmedicaltr…     

几种新的FBN1 cDNA片段的克隆及其在马凡综合症基因诊断中的意义

报道3种新的FBN1片段的DNA序列,并分析这些新序列在1例非典型性马凡综合症基因诊断中的参考意义.     

Molecular analysis for diagnosis of Marfan syndrome and Marfan-associated disorders

Marfan syndrome is a systemic disorder of connective tissue, caused by mutations in the FBN1, TGFBR1 or TGFBR2 genes. This syndrome is characterized by involvement of three major systems, skeletal, ocular, and cardiovascular. The continuing improvements in molecular biology and increasing availability of molecular diagnosis in clinical practice allow recognition of Marfan syndrome in patients with incomplete phenotypes. Additionally, molecular analyses could also be used for preimplantation genetic diagnosis. The identification of a mutation allows for early diagnosis, prognosis, genetic counseling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening.

     

马方综合征合并胸肺膈改变23例分析

目的了解马方综合征引起胸、肺、膈病变的情况。方法回顾性分析1990年1月至2006年6月在我院住院治疗且出院时诊断为马方综合征的65例患者的病历记录，分析病史、体格检查、X线胸片、CT检查等记录。结果23例患者（35％）有胸、肺、膈受累。有胸、肺、膈受累患者与无胸、肺、膈受累患者的平均年龄及性别分布差异无统计学意义。7例脊柱侧弯，7例胸廓畸形，5例胸腔积液，X线胸片诊断肺气肿4例，自发性气胸3例，2例膈疝。1例患者出现严重呼吸衰竭、肺源性心脏病。结论胸、肺、膈是马方综合征较易累及的部位，呼吸科医师应当加强对马方综合征的认识。     

A new frame-shifting mutation of UGT1A1 gene causes type I Crigler-Najjar syndrome

We present a case of severe persisting unconjugated hyperbilirubinemia in a Uigur infant boy, eventually diagnosed as Crigler-Najjar syndrome type I. DNA analysis of his blood of the UGT1A1 gene sequence demonstrated that he was homozygous for an insertion mutation causing a change of the coding exons with a frame-shift, resulting in the substitution of 27 abnormal amino acid residues in his hepatic bilirubin uridine diphosphoglucuronyl transferase enzyme. Both of his parents were heterozygous for the same mutation. A novel frame-shifting mutation of the UGT1A1 gene was found, confirming the diagnosis of Crigler-Najjar syndrome type I for this patient.