7个中国Kallmann综合征家系临床评估、基因测序及遗传学分析

发布时间：2018-05-19 03:35

本文选题：卡尔曼综合征（KS） + 特发性低促性腺激素性性腺功能减退症(IHH)　；参考：《中国人民解放军医学院》2013年硕士论文

【摘要】：目的：卡尔曼综合征(Kallmann Syndrome, KS)是特发性低促性腺激素性性腺功能减退症（Idiopathic hypogonadotropic hypogonadism，IHH）的一个独特生物模型，即有发育障碍，又有嗅觉异常。KS病因分自发性和遗传性。为进一步明确KS的基因突变及基因突变与临床表型的关系，本文研究了7个KS家系，并与散发KS及正常人对照。方法：研究7个KS家系，观察患者第二性征发育情况、嗅觉表型及其他临床表型；并对7个家系先证者分别行目前已知的除CHD7之外的所有KS或嗅觉正常的IHH(nIHH)相关基因（19个）（KAL-1、FGFR1、FGF8、PROKR2、PROK2、NELF、WDR11、HS6ST1、KISS1R、KISS1、TAC3、TACR3、LEPR、LEP、PCSK1、GNRHR、GNRH1、SEMA3A、NDN）外显子及外显子、内含子交接区域测序，并应用70例散发KS及200例健康中国人做对照。结果：家系1、2、7第二性征发育差、嗅觉重度或完全丧失；家系3、4、5、6第二性征和嗅觉症状轻重不一，并且有可逆性KS病例，呈现明显不完全外显性。7个家系中有5个家系检测出基因突变：KAL-1:p.R191ter纯和突变（家系1）；KAL-1:p.C13ter纯和突变（家系2）;FGFR1：p.R250W杂合突变（家系3）； PROKR2：p.Y113H纯和突变（家系4及家系5）。其中KAL-1:p.C13ter尚无文献报道，，是本文发现的新的突变位点。家系6及家系7未检测出任何基因变化。70例散发KS检测上述5个突变位点，发现PROKR2：p.Y113H的1个纯和突变和1个杂合突变，其余位点正常。200例正常对照中发现2个PROKR2：p.Y113H杂合突变，其余位点正常。结论： 1.7个家系中有5个家系检测出基因突变，其中发现KAL-1的一个新突变位点:c.C39A，p.C13ter。2.KS基因型及表型-基因型关系均十分复杂，有的遵循经典的单基因遗传模式，并可以受Lyon假说、延迟显性作用及微缺失影响。有的无法用单基因遗传模式解释，可能遵循二基因或寡基因遗传（可能有目前尚未发现的KS/nIHH相关基因参与），并受环境和表观遗传学因素影响。
[Abstract]:Objective: Kallmann Synmedrom (KSs) is a unique biological model of idiopathic hypogonadism hypogonadotropic hypogonadismHH. In order to further clarify the relationship between KS gene mutation and clinical phenotype, 7 KS families were studied and compared with sporadic KS and normal controls. Methods: Seven KS families were studied to observe the development of secondary sexual characteristics, olfactory phenotype and other clinical phenotypes. The exons and exons of all known KS or normal olfactory IHHnIHH genes (19 KKL-1FGFR1FGFR1 FGF8PROKR2FGF8PROKR2FGFR2FGF8PROKR2FGFR2FGF8PROKR2FGF8PROKR2FGFR2FGF8PROKR2FGFR2FGF8PROKR2FGFR2FGF8PROKR2FGFR2FGF8PROKR2FGFR2FGFR2FGF8PROKR2FGFR2FGF8PROKR2FGFR2FGF-8PROKR2FGFR2FGF8PROKR2FGF8PROKR2FGFR2FGF8PROKR2MAN HS6ST1KISS1KISS1TAC3CR3KISS1TAC3RACR3LEPREP PCSK1GNRHR-RH1@@ Results: The second sexual sign of 1 family was poor, the second sex sign was severe or lost completely, and the second sex sign and olfactory symptom were different in 3 families, and there were reversible KS cases. In 5 of the 7 families, the gene mutation: KAL-1: p.R191ter homologous and mutated (family 1: KAL-1: p.C13ter) and mutation (family 2FGFR1: p.R250W heterozygosity) were detected in 5 of the 7 families (family 3; PROKR2:p.Y113H homozygosity and mutation (family 4 and family 5). Among them, KAL-1:p.C13ter has not been reported in literature, and it is a new mutation site found in this paper. No gene changes were detected in families 6 and 7. 70 sporadic KS loci were detected. One pure mutation and one heterozygous mutation were found in PROKR2:p.Y113H, and 2 PROKR2:p.Y113H heterozygosity mutations were found in the other normal controls. The other sites are normal. Conclusion: 1. Gene mutations were detected in 5 of the seven families. One of the new mutation sites of KAL-1 was found to be the complex relationship between genotype and phenotypic relationship of KAL-1. Some of them follow the classical single gene genetic model and can be hypothesized by Lyon. Delayed dominance and microdeletion. Some of them can not be explained by single gene genetic model and may follow two genes or oligogenes (there may be genes related to KS/nIHH that have not been found at present and may be affected by environmental and epigenetic factors).
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R588;R3416

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