# Novel KISS1 Gene Mutation Leading to Male Hypogonadotropic Hypogonadism

## TL;DR

A new mutation in the KISS1 gene is found to cause male hypogonadotropic hypogonadism, with successful treatment through hormone therapy.

## Contribution

A novel heterozygous KISS1 variant c.-7C>T is identified as a cause of hypogonadotropic hypogonadism in two brothers.

## Key findings

- The KISS1 mutation affects the Kozak sequence and may disrupt gene expression.
- Testosterone therapy restored sex characteristics and hormone levels in both brothers.
- Combination hormone therapy enabled spermatogenesis and fatherhood in one patient.

## Abstract

The human
KISS1
gene encodes the hypothalamic Kisspeptin, which is
released in a pulsatile manner and binds the KISS1 receptor, that is located on
gonadotropin releasing hormone neurons. This interaction ensures pulsatile
gonadotropin releasing hormone secretion leading to induction of the
hypothalamic-pituitary-gonadal axis and by this controls puberty onset.
Disruption of this process is associated with hypogonadotropic hypogonadism. We
identified a novel heterozygous
KISS1
variant c.-7C>T in two brothers
diagnosed with hypogonadotropic hypogonadism. The mutation affects the Kozak
consensus sequence of the
KISS1
gene and potentially interferes with
KISS1
gene expression. Consequently, this affects the
hypothalamic-pituitary-gonadal axis resulting in hypogonadotropic hypogonadism.
In both patients, complete development of primary and secondary male sex
characteristics and stabilization of serum sex steroid hormone levels was
achieved by testosterone therapy. Additionally, human chorionic gonadotropin and
follicle stimulating hormone combination therapy in the older brother (patient
1) induced spermatogenesis and enabled fatherhood. Apart from this, we
identified the heterozygous
CHD7
variant c.2690G>A in the younger
brother (patient 2). However, the contribution of this variant to the
pathogenesis of hypogonadotropic hypogonadism remains elusive.