Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism

다국어 초록 (Multilingual Abstract)

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin‐releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Our study further showed the contribution of SEMA3A loss‐of‐function variants to the pathogenesis of IHH.







In this study, we identified three novel SEMA3A mutations in three unrelated Chinese IHH patients by exome sequencing. Functional studies indicated that the three mutant proteins led to reduction of FAK phosphorylation level in GN11 cells, and could not induce effective migration of GN11 cells. Furthermore, the V458I mutant protein had secretory defects.