We will review neuropathies and clinical presentations that result from the disruption of NGF signalling in HSAN type IV and HSAN type V and review current advances in developing anti-NGF therapy for the clinical management of pain.
We have studied a large Swedish family with a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V).
To prevent the NGF pain-inducing collateral effects, thus avoiding the necessity for local brain injection, we developed painless NGF (hNGFp), based on the human genetic disease Hereditary Sensory and Autonomic Neuropathy type V (HSAN V). hNGFp has similar neurotrophic activity as wild type human NGF, but its pain sensitizing activity is tenfold lower.
These results provide a basis for elucidating the mechanisms underlying the clinical manifestations of HSAN V patients, and provide a basis for the development of "painless" hNGF molecules with therapeutic potential.
The physiological function of NGF as a pain mediator is altered in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), caused by the 661C>T transition in the <i>Ngf</i> gene, resulting in the R100W missense mutation in mature NGF.
The integration of both TrkA and p75<sup>NTR</sup> signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.<b>SIGNIFICANCE STATEMENT</b> In the present study, we characterized the naturally occurring nerve growth factorNGF<sup>R100W</sup> mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGF<sup>R100W</sup> retains trophic support capability through TrkA, but fails to engage p75<sup>NTR</sup> signaling pathways.
No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V.
No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V.
Generation of the human induced pluripotent stem cell line UKWNLi002-A from dermal fibroblasts of a woman with a heterozygous c.608 C>T (p.Thr203Met) mutation in exon 3 of the nerve growth factor gene potentially associated with hereditary sensory and autonomic neuropathy type 5.
Although those HSAN V patients associated with the NGF<sup>R100W</sup> mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGF<sup>R100W</sup> mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved.
A point mutation (R100W) in the NGFB gene was found in patients with Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), which leads to pain insensitivity.