CAJ | 학술논문

目的：分析 Kallmann 综合征( Kallmann syndrome, KS)患者 KS1( Kallmann syndrome 1, KAL1),前动力蛋白2(prokineticin 2,PROK2)和前动力蛋白受体2(prokineticin receptor 2,PROKR2)3个基因的突变情况。方法①采用放射免疫分析法检测激素水平,超声扫描评估腹部结构,脑部磁共振成像(magnetic resonance imaging,MRI)检测嗅球、脑沟和内耳的结构。②运用聚合酶链式反应(polymerase chain reaction,PCR),结合 PCR 产物直接测序技术分析 KAL1、PROK2和 PROKR23个基因外显子突变。③分别利用 SIFT、Polyphen 和 Mutation Taster 3种生物信息学平台进行了错义位点和多态性位点的功能分析。结果①患者青春期发育不良,嗅觉减退,其父母无症状。②在患者基因组中找到2个 KAL1杂合突变位点(Ile 565 Thr 和 Ser 570 Thr),5个 KAL1基因单核苷酸多态性位点(single nucleotide polymorphism,SNP)：Val 534 Ile、Val 560 Phe、Gly 567 Ser、Lys 666 Met和 Agr 668 His,以及一个 PROKR2纯合突变位点(Tyr 113 His)。同时也在患者父母基因组中检测到 PROKR2杂合突变位点(Y113H)。③生物信息学分析结果显示 I565T、S570T 和 Y113H(PROKR2)3个位点可能是该患者的致病基因位点。结论这2个新的突变位点还未在中国人群中报道过,这也是国内报道的第1例同时带有2个 KAL1突变和一个 PROKR2突变的 KS 患者,表明该患者可能是一个双基因遗传的 KS 患者。
목적：분석 Kallmann 종합정( Kallmann syndrome, KS)환자 KS1( Kallmann syndrome 1, KAL1),전동력단백2(prokineticin 2,PROK2)화전동력단백수체2(prokineticin receptor 2,PROKR2)3개기인적돌변정황。방법①채용방사면역분석법검측격소수평,초성소묘평고복부결구,뇌부자공진성상(magnetic resonance imaging,MRI)검측후구、뇌구화내이적결구。②운용취합매련식반응(polymerase chain reaction,PCR),결합 PCR 산물직접측서기술분석 KAL1、PROK2화 PROKR23개기인외현자돌변。③분별이용 SIFT、Polyphen 화 Mutation Taster 3충생물신식학평태진행료착의위점화다태성위점적공능분석。결과①환자청춘기발육불량,후각감퇴,기부모무증상。②재환자기인조중조도2개 KAL1잡합돌변위점(Ile 565 Thr 화 Ser 570 Thr),5개 KAL1기인단핵감산다태성위점(single nucleotide polymorphism,SNP)：Val 534 Ile、Val 560 Phe、Gly 567 Ser、Lys 666 Met화 Agr 668 His,이급일개 PROKR2순합돌변위점(Tyr 113 His)。동시야재환자부모기인조중검측도 PROKR2잡합돌변위점(Y113H)。③생물신식학분석결과현시 I565T、S570T 화 Y113H(PROKR2)3개위점가능시해환자적치병기인위점。결론저2개신적돌변위점환미재중국인군중보도과,저야시국내보도적제1례동시대유2개 KAL1돌변화일개 PROKR2돌변적 KS 환자,표명해환자가능시일개쌍기인유전적 KS 환자。
Objective To analyze the mutation of Kallmann syndrome 1(KAL1), prokineticin(PROK2) and prokineticin receptor 2 (PROKR2) in a family, which has a 13-year-old son with Kallmann syndrome(KS). Methods ① Hormone levels were measured by immunoradiometric assay, abdomen structures were assessed by abdominal ultrasound scan, brain magnetic resonance imaging(MRI) was used to visualize the olfactory bulbs, sulci, and inner ears; ② The exon sequences of the three genes(KAL1, PROK2 and PROKR2) were screened for a mutation by direct sequencing; ③ SIFT, Polyphen and MutationTaster were used as a complementary approach to assess the significance of polymorphisms and missense mutations. Results ① The patient had sexual infantilism, and the MRI of the head revealed the dysplasia of olfactory bulbs and olfactory tract; the parents of this patient had normal pubertal development, serum gonadotropin and estradiol concentrations, and their MRI results showed normal olfactory bulbs; ② In KAL1 gene, two novel mutations(I565T and S570T) and five previously described polymorphisms(V534I, V560F, G567S, K666M and R668H) were detected in this patient. In PROKR2 gene, a homozygous Y113H was presented in this patient, and this mutation was also detected in the heterozygous state in his parents; ③I565T, Y113H (PROKR2) and S570T may be the harmful variation according to our stringent analysis. Conclusion To date, these two novel mutations have not yet been reported in the Chinese population, and this is the first case of KS patient who exhibited two-point mutation in KAL1 and was also carried a missense mutation in PROKR2, thus indicating a possible digenic inheritance of the disease in this individual.