CAJ | 학술논문

目的分析1例汉族经典型枫糖尿病新生儿的临床特点及其相关基因的致病性突变.方法患儿男,生后8d因喂养困难于2013年4月转来上海交通大学附属儿童医院,收集患儿的临床资料及影像学检查等明确诊断后,提取患儿及其父母的外周血白细胞DNA检测BCKDHA、BCKDHB、DBT和DLD基因,确定患儿的基因突变位点,并进行生物信息学分析.结果患儿表现为生后喂养困难、抽搐、代谢性酸中毒、尿有枫糖味等,CT示广泛脑白质低密度改变,串联质谱及尿气相色谱-质谱均符合枫糖尿病的诊断.基因测序结果在BCKDHB基因上发现2个错义突变:c.580 C＞T(p.Leu194Phe)和c.597 T＞G(p.Ser199Arg),均为杂合子,且为国际上未报道过的新突变.经Sanger测序发现其父亲携带了错义突变p.Leu194Phe,其母亲携带了错义突变p.Ser199Arg,符合家系共分离规律.PolyPhen蛋白功能预测发现此2个错义突变为有害的,很可能影响其蛋白功能.结论 BCKDHB基因c.580 C ＞T(p.Leu194Phe)和c.597 T＞G(p.Ser199Arg)复合杂合突变是该患儿的致病性突变,是该枫糖尿病患儿临床表现的基因分子基础,且为国际上未报道过的新突变.
목적 분석1례한족경전형풍당뇨병신생인적림상특점급기상관기인적치병성돌변.방법 환인남,생후8d인위양곤난우2013년4월전래상해교통대학부속인동의원,수집환인적림상자료급영상학검사등명학진단후,제취환인급기부모적외주혈백세포DNA검측BCKDHA、BCKDHB、DBT화DLD기인,학정환인적기인돌변위점,병진행생물신식학분석.결과 환인표현위생후위양곤난、추휵、대사성산중독、뇨유풍당미등,CT시엄범뇌백질저밀도개변,천련질보급뇨기상색보-질보균부합풍당뇨병적진단.기인측서결과재BCKDHB기인상발현2개착의돌변:c.580 C＞T(p.Leu194Phe)화c.597 T＞G(p.Ser199Arg),균위잡합자,차위국제상미보도과적신돌변.경Sanger측서발현기부친휴대료착의돌변p.Leu194Phe,기모친휴대료착의돌변p.Ser199Arg,부합가계공분리규률.PolyPhen단백공능예측발현차2개착의돌변위유해적,흔가능영향기단백공능.결론 BCKDHB기인c.580 C ＞T(p.Leu194Phe)화c.597 T＞G(p.Ser199Arg)복합잡합돌변시해환인적치병성돌변,시해풍당뇨병환인림상표현적기인분자기출,차위국제상미보도과적신돌변.
Objective Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder that is caused by mutations in the subunits of the branched chain α-ketoacid dehydrogenase (BCKD) complex.This report presents a Han ethnic Chinese newborn infant with the severe classic form of MSUD caused by two novel missense mutations in the BCKDHB gene.Method The clinical and biochemical data of a Chinese neonate with classic form of MSUD were analyzed,and the DNA sequences of BCKDHA,BCKDHB,DBT and DLD genes were investigated for mutations.Then the DNA samples of the proband and the patient's parents were tested with Sanger sequencing.Result The manifestations of this patient were poor feeding,low reaction,and compensatory metabolic acidosis.Tandem mass spectrometry (MS/MS) showed that leucine and valine were significantly higher than normal.Urine gas chromatographymass spectrometry (GC/MS) showed significant abnormality.Brain CT scan showed white matter changes.We identified two previously unreported mutations in the BCKDHB gene,p.Leu194Phe (c.580 C ＞ T) and p.Ser199Arg (c.597 T ＞ G) in exon 5.Segregation analysis showed that the novel mutation p.Ser199Arg was maternally inherited and the novel mutation p.Leu194Phe was paternally inherited.Neither mutation was found in the 186 alleles of 93 normal Han ethnic Chinese individuals.In human BCKDHB protein crystal structure,the 194th and 199th amino acids changes are likely to affect the spatial structure of the protein.The 194th and 199th amino acid of human BCKDHB protein was conserved among species.PolyPhen protein function prediction indicated that the 194th and 199th amino acid changes were likely to affect protein function.Conclusion Two novel missense mutations were identified in the BCKDHB gene in the Chinese patient with MSUD.