Hardelin J P, Petit C
Chargé de Recherche à l'INSERM, Unité de Génétique Moléculaire Humaine, Institut Pasteur, Paris, France.
Baillieres Clin Endocrinol Metab. 1995 Jul;9(3):489-507. doi: 10.1016/s0950-351x(95)80553-2.
The human KAL gene is responsible for the X chromosome-linked Kallmann's syndrome, which consists of an association between hypogonadotropic hypogonadism and anosmia (or hyposmia). Additional symptoms are occasionally observed. The olfactory defect is associated with hypoplasia of the olfactory bulbs and tracts. The hypogonadism may be due to a defect in the embryonic migratory process of GnRH-synthesizing neurones from the olfactory pits up to the brain. The human and chicken KAL genes have been isolated. From the amino acid sequences deduced, it has been postulated that the KAL protein is an extracellular matrix component, with putative antiprotease activity and adhesion function. Various point mutations and, in a few cases, deletions of KAL have been detected in patients. By in situ hybridization, KAL expression has been studied during embryonic development in the chick. From embryonic day 2 (ED2) to ED8, the KAL gene is expressed in various endodermal, mesodermal and ectodermal derivatives, whereas the expression from ED8 is almost entirely restricted to definite neuronal populations in the central nervous system, most of which still express the gene after hatching. According to such a spatiotemporal pattern of expression, we suggest that the KAL gene is involved both in morphogenetic events and in late neuronal differentiation and/or neuronal trophicity. With respect to the olfactory system, the KAL gene is expressed in the mitral cells of the olfactory bulbs from ED8 onwards. In contrast, no expression of the KAL gene is detected at any stage in either the embryonic olfactory epithelium or the surrounding nasal mesenchyme. Therefore, assuming that similar conditions are found in the human embryo, we suggest that the olfactory anomaly in X-linked Kallmann's syndrome results from a central target cell defect. Current hypotheses regarding the pathophysiology of the GnRH deficiency are also discussed. In situ hybridization experiments in the human embryo, as well as characterization of the KAL protein, are in progress.
人类KAL基因与X染色体连锁的卡尔曼综合征有关，该综合征表现为低促性腺激素性性腺功能减退与嗅觉缺失（或嗅觉减退）相关联。偶尔还会观察到其他症状。嗅觉缺陷与嗅球和嗅束发育不全有关。性腺功能减退可能是由于合成促性腺激素释放激素（GnRH）的神经元在胚胎期从嗅窝向脑部迁移过程中出现缺陷所致。人类和鸡的KAL基因已被分离出来。根据推导的氨基酸序列推测，KAL蛋白是一种细胞外基质成分，具有假定的抗蛋白酶活性和黏附功能。在患者中已检测到KAL基因的各种点突变，少数情况下还存在缺失。通过原位杂交技术，对鸡胚胎发育过程中的KAL表达进行了研究。从胚胎第2天（ED2）到ED8，KAL基因在各种内胚层、中胚层和外胚层衍生物中表达，而从ED8开始，其表达几乎完全局限于中枢神经系统中的特定神经元群体，其中大多数在孵化后仍表达该基因。根据这种时空表达模式，我们认为KAL基因既参与形态发生事件，也参与后期神经元分化和/或神经元营养作用。关于嗅觉系统，从ED8开始，KAL基因在嗅球的二尖瓣细胞中表达。相反，在胚胎期的嗅觉上皮或周围的鼻间充质中，在任何阶段都未检测到KAL基因的表达。因此，假设在人类胚胎中也存在类似情况，我们认为X连锁卡尔曼综合征中的嗅觉异常是由中枢靶细胞缺陷引起的。文中还讨论了目前关于GnRH缺乏病理生理学的假说。人类胚胎的原位杂交实验以及KAL蛋白的特性研究正在进行中。
