CHL1基因突变在Kallmann综合征发病中的作用及机制研究

Kallmann Syndrome(KS) is a genetic disorder associating congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and congenitally absent or impaired sense of smell. KS is related to defective in migration of olfactory nerve endings and GnRH neurons. In addition to absence of puberty and infertility, KS can sometimes cause multiple system dysfunction including abnormalities in renal, neuron and skeletal systems, which has serious adverse effects on physical and mental health of the patients. Mutations in so far identified genes responsible for KS account for less than 50% of the KS cases. In our previous study, we identified a mutation in CHL1 gene from a Chinese KS family by Whole exons sequencing. The protein encoded by CHL1 is a member of the L1 gene family of neural cell adhesion molecules which may play a role in regulating cell migration in nervous system development. In order to further investigate the role and mechanism of this mutation in the pathogenesis of KS, we will use the mice GnRH neuroblastoma cell model and construct the CHL1 mutant mouse model to study the effects of the mutated protein on the migration of GnRH neurons and olfactory axons. Our study will identify a new KS causative gene and reproductive endocrine regulation factor which has important implications in the gene diagnosis, genetic counseling, individualized treatments and preplantation genetile diagnosis which aims to blocking the inheritance of this disease.

Kallmann综合征（Kallmann Syndrome, KS），是一种以下丘脑促性腺激素释放激素（Gonadotropin-releasing hormone, GnRH）分泌不足并嗅觉障碍为特征的遗传异质性疾病，主要表现为青春发育障碍及不育，可伴有神经、骨骼、肾脏等多系统异常，严重威胁患者身心健康。KS的发病机制是基因缺陷导致GnRH神经元与嗅神经轴突迁移受损，目前已知致病基因仅能解释约50%的病例。申请者前期通过全外显子测序在一个中国KS家庭中分离出了一个CHL1基因突变，该基因编码一个与神经迁移有关的神经细胞粘附分子。我们下一步拟体外研究该突变对GnRH神经瘤细胞迁移的影响，并构建基因突变小鼠模型在体研究该突变对GnRH神经元及嗅神经迁移的影响。我们拟鉴定出一个新的KS致病基因暨生殖内分泌调控因子，对KS的基因诊断、遗传咨询、个体化治疗及胚胎植入前诊断阻断疾病遗传具有重要意义。

Kallmann综合征（Kallmann Syndrome, KS），是一种以下丘脑促性腺激素释放激素（Gonadotropin-releasing hormone, GnRH）分泌不足并嗅觉障碍为特征的遗传异质性疾病，主要表现为青春发育障碍及不育。KS的发病机制是基因缺陷导致GnRH神经元与嗅神经轴突迁移受损，目前已知致病基因仅能解释约50%的病例。我们前期通过全外显子测序在一个中国KS家庭中分离出了一个CHL1基因突变，生物信息学分析提示该基因突变为致病突变，我们拟通过体外体内研究证明该基因为Kallmann综合征的致病基因。我们首先在体外研究该突变对Gn11细胞迁移的影响。研究发现，CHL1作为胞内蛋白可以促进Gn11细胞迁移，但是野生型CHL1和突变型CHL1对Gn11细胞迁移的影响无明显差异，证明该基因突变不是导致KS的病因。研究小组随后在1例伴有先天性虹膜发育不全、两例虹膜正常的KS患者中分离出了3个PAX6基因突变，PAX6是一个转录因子基因，生物信息学分析提示该突变可影响蛋白功能。我们的体外研究证实，PAX6突变可通过降低调低Sema3a通路，进而减弱Gn11细胞的迁移，但对其增值及凋亡无影响。在此基础上，我们进一步构建了PAX6基因条件性敲除模型小鼠，对该基因与KS的关系进行进一步研究，该模型小鼠目前处于进一步繁殖中。