Posttranslational Modification Defects in Fibroblast Growth Factor Receptor 1 as a Reason for Normosmic Isolated Hypogonadotropic Hypogonadism.

Some mutations in affect the sense of smell while others do not, resulting in Kallmann syndrome (KS) and normosmic isolated hypogonadotropic hypogonadism (nIHH), respectively. The underlying mechanism is still unclear. variants are found in less than 10% of patients with KS and nIHH, and among them, only some have undergone functional analysis. Thus, the correlation between the phenotype and genotype cannot be clearly verified. This study reports a case of nIHH and explores the potential mechanism of the gene in the pathogenesis of nIHH. A preschooler with cryptorchidism, micropenis, strabismus, and hypopsia is described. As he had a normal sense of smell, he was diagnosed with nIHH. A de novo mutation in (c.2008G>A) was detected in the patient along with a novel variant in (c.964G>A) inherited from his mother. We present compelling in vitro evidence that this mutation-induced posttranslational modification defect, including defective glycosylation and impaired -autophosphorylation, along with the final reduction in expression, could lead to impairment of the receptor and abnormal signaling and eventually result in developmental abnormalities and inhibition of GnRH neuron release. The identification of an additional variant suggests that might play a potential role in GnRH development.