Familial X-linked Kallmann's syndrome appears is due to a defect localised to the Xp 22.3 region on the small arm or the X chromosome.
The predicted protein has significant similarities with proteins involved in neural cell adhesion. Loss of this protein may explain the failure of GnRH neurones to migrate from above the cribriform plate to the hypothalamus.
- KAL1 gene has been linked to KS and is the best-characterized gene related to GnRH deficiency
- gene has been mapped to X-chromosome region Xp22.32 and consists of 14 exons
- encodes the protein anosmin-1, which is an extracellular adhesion protein that plays a possible role in orchestrating GnRH neuron adhesion and axonal migration
- most KAL-1 mutations are nucleotide insertions or deletions that result in frame shift mutations or a premature stop codon
- mutations in this gene lead to a GnRH migration and olfactory neuron disorder
- failure of GnRH neurons to migrate from the olfactory placode to their destination in the hypothalamus and olfactory lobe represents the basic embryological defect of this syndrome
- KAL-1 gene accounts for the X-linked recessive mode of inheritance of familial KS and 10-20% of all KS cases (1,2)
- FGR1, GNRHR, NELF, GPRS54, PROK-2, PROKR-2, CHD-7 and FGF-8 genes have also been linked to this syndrome.
Reference:
- Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5(10):569-76.
- Viswanathan V, Eugster EA. Etiology and treatment of hypogonadism in adolescents. Pediatr Clin North Am. 2011;58(5):1181-200.