Kallmann syndrome type 1
Tuesday 20 March 2007
Kallmann syndrome consists of congenital, isolated, idiopathic hypogonadotropic hypogonadism and anosmia.
The gene responsible for the X-linked form of Kallmann syndrome, KAL1, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus.
olfactory lobe agenesis
decreased sexual hair
partial or complete anosmia in some heterozygous females
mirror hand movements (bimanual synkinesia)
- unilateral renal agenesis
- multicystic renal dysplasia
hypothalamic gonadotropin-releasing hormone (GnRH) deficiency
impaired FSH and LH secretion
Leydig cell insensitivity to gonadotropin
The X-linked form results from mutations of KAL1, which encodes the extracellular matrix protein anosmin-1.
KAL1 transcripts occur in the human metanephros and olfactory bulb from 45 days of gestation. These sites are consistent with organs affected in KS.
Anosmin-1 immunolocalizes to basement membrane of human UB branches. With increased understanding of anosmin-1 structure and function in different organisms, these observations can start to be synthesized into potential mechanisms of maldevelopment.
Anosmin-1 is a modular protein consisting of an N-terminal cysteine-rich region, a whey acidic protein–like 4 disulfide core motif (WAP), four contiguous fibronectin-like type III (FnIII) domains, and a histidine-rich C-terminus.
Similar WAP- and FnIII-encoding domains occur in predicted KAL proteins in birds, fish, flies, and worms.
In the absence of a rodent model, KAL1 function has been investigated in C. elegans: Worm Kal1 mutants have defects in ventral closure and male tail formation, partially rescued by the human gene, suggesting conservation of function across species, and neuronal targeting studies implicate FnIII domains in control of axon branching and both FnIII and WAP domains in axon misrouting.
The FnIII domains are predicted to be involved in anosmin-1–HSPG interactions, and heparan-6-O-sulfotransferase, an enzyme required for the formation of cell membrane–associated HSPG, was identified as a modifier of KAL1-induced axonal defects in C. elegans.
HSPG are not only important in neural development, particularly in neurite outgrowth and migration, but they also have critical roles in nephrogenesis: Mice homozygous for a gene trap mutation in heparan sulfate 2-sulfotransferase, for example, fail to initiate normal metanephrogenesis, as do mutants lacking glial cell line–derived neurotrophic factor or its receptors, and signaling via this pathway also requires heparan sulfate proteoglycan (HSPG1) or syndecan-2 (SDC2).
Loss of function mutations in FGFR1 have recently been reported in dominantly inherited Kallmann syndrome type 2 (KAL2), and binding of HSPG1 (SDC2) to FGF and its receptors is also required for FGF signaling.
- Kallmann syndrome type 2 (KAL2 at 8p11)
- Kallmann syndrome type 3 (KAL3 at 20p13)
- Kallmann syndrome type 4 (KAL4 at 3p21)
- Kallmann syndrome with spastic paraplegia (MIM.308750)
- Kallmann syndrome with brachytelephalangy with characteristic facies(MIM.308750)