CAJ | 학술논문

背景研究已证实,c.365A＞T和c.658_66 0delAAG突变是甲基丙二酸尿症合并同型半胱氨酸血症cblC型(cblC病)散发患者MMACHC基因突变少见的类型,且目前尚未见到相关的家系报道. 目的对患cblC病的中国一家系进行临床和分子遗传学分析.方法本研究遵循Helsinki宣言,所有检测方法均征得患儿父母的知情同意.收集一个2代4名成员的cblC病中国家系,包括患病兄妹和正常表型的父母.对所有成员进行详细的眼部检查,包括视力、裂隙灯显微镜、检眼镜检查及眼底照相、眼压测量等.采集4名家系成员的外周血进行基因组DNA的提取,通过PCR检测和DNA直接测序法筛选该疾病相关MMACHC基因的序列改变.结果该家系符合常染色体隐性遗传方式,先证者及胞妹均为cblC病患儿,分别于10岁及1岁时确诊并给予相关治疗,其父母表型均正常.2例患儿眼前节未见异常,但先证者存在双侧眼球震颤,黄斑部萎缩斑明显大于其胞妹.DNA测序结果分析表明,2例患儿均存在MMACHC基因4号外显子缺失突变(c.658_660delAAG,p.K220delLys)和3号外显子错义突变(c.365A＞T,p.H122L)组成的复合杂合突变,而表型正常的母亲存在第3外显子编码区365位A＞T杂合突变,密码子由CAT变为CTT,表型正常的父亲在第4外显子编码区第658 _660位缺失AAG 3个碱基. 结论该cblC病家系是由MMACHC基因的c.658_660delAAG和c.365A＞T复合杂合突变导致,MMACHC基因在该病具有致病作用.
배경 연구이증실,c.365A＞T화c.658_66 0delAAG돌변시갑기병이산뇨증합병동형반광안산혈증cblC형(cblC병)산발환자MMACHC기인돌변소견적류형,차목전상미견도상관적가계보도. 목적 대환cblC병적중국일가계진행림상화분자유전학분석.방법 본연구준순Helsinki선언,소유검측방법균정득환인부모적지정동의.수집일개2대4명성원적cblC병중국가계,포괄환병형매화정상표형적부모.대소유성원진행상세적안부검사,포괄시력、렬극등현미경、검안경검사급안저조상、안압측량등.채집4명가계성원적외주혈진행기인조DNA적제취,통과PCR검측화DNA직접측서법사선해질병상관MMACHC기인적서렬개변.결과 해가계부합상염색체은성유전방식,선증자급포매균위cblC병환인,분별우10세급1세시학진병급여상관치료,기부모표형균정상.2례환인안전절미견이상,단선증자존재쌍측안구진전,황반부위축반명현대우기포매.DNA측서결과분석표명,2례환인균존재MMACHC기인4호외현자결실돌변(c.658_660delAAG,p.K220delLys)화3호외현자착의돌변(c.365A＞T,p.H122L)조성적복합잡합돌변,이표형정상적모친존재제3외현자편마구365위A＞T잡합돌변,밀마자유CAT변위CTT,표형정상적부친재제4외현자편마구제658 _660위결실AAG 3개감기. 결론 해cblC병가계시유MMACHC기인적c.658_660delAAG화c.365A＞T복합잡합돌변도치,MMACHC기인재해병구유치병작용.
Background Researches determined that c.365A＞T and c.658_66 0delAAG variant is rare type of MMACHC gene mutation in the patients with cobalamin C (CblC) type methylmalonic aciduria and homocystinuria (cblC disease).What is more,the cblC disease family with the same mutation has not been reported up to now.Objective This study was to detect and analyze the mutations in MMACHC gene in a Chinese family with cblC disease.Methods This protocol complied with Helsinki declaration,and all the medical examination were performed under the informed consent of custodian.The Chinese family was composed of four members of the two generations,including a 14-year male proband,his 4-year sister,their mother and father.All members of the family underwent complete ophthalmologic examinations covered with the ocular anterior segment and posterior segment.The peripheral blood as collected for the families for the extraction of DNA.All exons of MMACHC gene were screened for sequence alterations by PCR and direct DNA sequencing.Results The cblC disease family was verified to be anautosomal recessive inheritance.The proband and his sister appeared to be the cblC disease children and their parents were phenotypic normal.The sickened children were diagnosed and managed at 10 years old and 1 year old,respectively.No obvious abnormal finding was seen in the anterior ocular segment,but different degrees of macular atrophies were seen in both eyes of the children.In addition,nystagmus was found in the proband.The compound heterozygote mutations in the MMACHC gene were identified in two affected children,which included a deletion mutation (c.658_660delAAG,p.KdelLys) in exon 4 and a missense mutation (c.365A＞T,p.H122L) in exon 3,both of them were respectively inherited from their unaffected parents.However,c.365A＞T variant was sequenced in the phenotypica normal mother,and c.658_660delAAG variant was found in the phenotypica normal father.Conclusions A rare compound heterozygote mutation of MMACHC is identified in this Chinese family,indicating MMACHC may play a critical role in the development of cblC disease.