Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism

The pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH) is genetically complex. The aims of this study were to investigate the genetic profile and clinical manifestation of IHH in a Chinese pedigree and to discover new IHH-associated genes.

The first step was to follow up the clinical phenotype and therapeutic outcomes of the pedigree in university hospital. The second step was that mutation screening was performed in this pedigree and 100 healthy controls. The third step was to further verify the pathogenicity of the discovered rare sequencing variant (RSV) by functional experiments. Whole exome sequencing, Sanger sequencing, testicular volume (TV), semen analysis, assessment of cell migration and necroptosis were performed.

One heterozygous RSV (p.G517E) in CHL1 was identified in two male IHH patients and their mother in the pedigree, but not in healthy controls. All the three individuals exhibited olfactory impairment. hCG/hMG treatment significantly improved TV, serum testosterone and/or semen parameters of the two male patients. Functional analysis indicated that CHL1 significantly regulated GnRH neuronal cell line (GN11 cells) migration and necroptosis, with alteration of ERK1/2 activation, calcium loading, and transcription of RIPK3 and MLKL. However, the above processes were negatively influenced by the CHL1 RSV.

Our study reports the genetic relevance of CHL1 in IHH, and characterizes the phenotypic and therapeutic profiles in patients carrying the CHL1 RSV. CHL1 may act as a new IHH-associated gene, and should be taken into consideration in future investigations for this field.