DCC – Kallmann syndrome

Congenital hypogonadotropic hypogonadism (CHH) encompasses a group of disorders characterized by absent or incomplete puberty and infertility due to GnRH deficiency. A subset of CHH, Kallmann syndrome (KS), is defined by the additional feature of anosmia (HP:0000458) ([PMID:29202173]). The genetic architecture of KS is heterogeneous, with >30 genes implicated in ~50% of cases. DCC (deleted in colorectal cancer), encoding the Netrin-1 receptor, has emerged as a contributor to GnRH neuron development.

DCC is a transmembrane protein that binds the guidance cue Netrin-1 to direct commissural axon growth and neuronal migration. In mouse models, Dcc knockout leads to disrupted GnRH neuron ontogeny, mirroring KS features. The receptor contains multiple fibronectin type-III (FN3) domains essential for ligand interaction and downstream signaling.

Whole-exome sequencing of 133 CHH probands identified rare heterozygous DCC variants in six unrelated individuals ([PMID:29202173]), five of whom presented with KS ([PMID:29202173]). Two KS probands carried additional heterozygous NTN1 variants, supporting an oligogenic inheritance model in KS ([PMID:29202173]). All identified DCC variants were absent from population databases and predicted damaging by in silico tools.

The inheritance pattern is consistent with autosomal dominant transmission with variable expressivity and incomplete penetrance. Although formal segregation analyses were limited, the absence of these variants in controls and their recurrence in KS probands support pathogenicity. No definitive recurrent or founder variants have been reported for DCC in KS to date.

Functional studies in immortalized GnRH neurons (GN11 cells) demonstrate that DCC variants impair Netrin-1–mediated cell migration and alter intracellular signaling, leading to morphological defects consistent with deficient GnRH neuron migration ([PMID:29202173]). Rescue experiments and in vivo mouse models confirm that reduced DCC function disrupts hypothalamic GnRH neuron positioning.

Integrating genetic and functional data, heterozygous DCC variants contribute to KS pathogenesis via haploinsufficiency and perturbed Netrin-1 signaling. While additional genes and oligogenic interactions influence phenotype, DCC testing should be included in KS diagnostic panels. Key take-home: DCC heterozygous variants are a moderate evidence contributor to KS and inform genetic counseling and targeted investigation.

References

• Human molecular genetics • 2018 • DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development. PMID:29202173

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