F1000Prime Recommendation of [Young J et al., Hum Reprod 2012]

Despite several genes having been found mutated in patients affected by Kallmann's syndrome (KS) and hypogonadotropic hypogonadism (HH), the majority of cases (>60%) still has no causative gene, suggesting that additional disease loci remain to be identified. The discovery of the involvement of the semaphorin 3A (SEMA3A) gene in KS is of great value for a better genetic framework and counselling of the disease. In this research article, the authors report that a heterozygous deletion in the SEMA3A gene cosegregates with a KS phenotype. SEMA3A belongs to the class 3 semaphorins, a family of secreted molecules that modulate axonal guidance and neuronal migration events in the developing nervous system, and exert their actions by binding to neuropilins (NRP1 and NRP2) and plexins. Recently, by combining the analysis of genetically altered mice with in vitro models, we reported an essential role of SEMA3A in the development of the gonadotropin-releasing hormone (GnRH) neurons (see {1}, on which we are both authors), the population of hypothalamic neurons that exerts the physiological control of the reproductive axis. A defect in migration of GnRH neurons has been involved in the pathogenesis of the X-linked form of KS. Strikingly, mice lacking SEMA3A, or its signalling through both NRP1 and NRP2, recapitulate the anatomical features of altered GnRH neuron migration observed in KS. Therefore, this report is an important clinical confirmation of results obtained in animal and cell models. On the other hand, the defects observed in mice may be suggestive of an impairment of GnRH neuron migration also in this KS patient. These results indicate that genomic sequencing analysis and studies on animal/cell models of KS/HH may synergistically interact to lead to a better elucidation of the pathogenesis of these diseases. The findings reported in the study have a broad significance in the search of new candidate genes responsible for more than 60% of the idiopathic forms of HHs. SEMA3A gene analysis must be included in the genetic screening of idiopathic HH. References 1. Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. Cariboni A, Davidson K, Rakic S, Maggi R, Parnavelas JG, Ruhrberg C Hum Mol Genet 2011 Jan 15; 2(20):336-44 PMID: 2105970