Department of Clinical Laboratory, The Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan, China.
Health Management Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mol Genet Genomic Med. 2021 Nov;9(11):e1816. doi: 10.1002/mgg3.1816. Epub 2021 Oct 11.
Isolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin-releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans.
The aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis.
We identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH-associated genes.
Our study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss.
孤立性促性腺激素低下性性腺功能减退症（IHH）是一种临床综合征，其特征是由于促性腺激素释放激素（GnRH）的合成、分泌或作用缺陷导致性腺功能衰竭。分泌的糖蛋白 SEMA3A 与其受体 NRP1 或 NRP2 和 PLXNA 结合，参与轴突投射、树突分支、突触形成和神经元迁移。SEMA3A、NRP1、NRP2 和 PLXNA1 的缺乏与小鼠 GnRH 神经元发育异常和人类 IHH 有关。
本研究旨在通过全外显子组测序和家系分析，在中国的 IHH 先证者大样本中检查 NRP1、NRP2 和 PLXNA1 基因的基因型和表型谱。
我们在中国人 IHH 患者中发现了 10 个 PLXNA1 错义杂合变异，5 个 NRP1 错义杂合变异，2 个 NRP2 错义杂合变异。NRP1 变异仅存在于嗅觉缺陷的 IHH 患者（即 Kallmann 综合征，KS）中。此外，85%（17/20）的患者携带其他 IHH 相关基因的变异。
本研究极大地丰富了 IHH 中 PLXNA1、NRP1 和 NRP2 的基因型和表型谱。它可能有助于携带 PLXNA1、NRP1 和 NRP2 基因突变的 IHH 的遗传咨询、诊断和治疗。此外，我们的结果表明 NRP1 与听力损失密切相关。
