A congenital pain insensitivity mutation in the nerve growth factor gene uncouples nociception from affective pain in heterozygous humans and mice

Abstract

Pain is an unpleasant but necessary sensory experience, which facilitates adaptive behaviours, such as fear. Despite recent advances, the question of how the pain experience influences learning of the fear response is still debated 1,2 . Genetic disorders rendering patients congenitally unable to feel pain have been described, and are usually explained by defects in peripheral nociceptors 3-5 . It is not known how growing up without pain affects central emotional and motivational responses to aversive stimuli. The rare autosomal recessive Hereditary Sensory and Autonomic Neuropathy type V (HSAN V) is caused by a mutation in the nerve growth factor (NGF) gene (R100W). HSAN V homozygous patients display a congenital indifference to painful events, with deficits in peripheral nociceptors but without overt cognitive impairment 6 . In contrast, heterozygous carriers do not present with pain-related deficits and have been identified only through pedigree and genetic screening 7,8 . We exploited this clinically silent population to dissociate nociceptive from affective features of pain. To address this we investigated both heterozygous knock-in mice bearing the R100W mutation (NGF R100W/m mice) and a cohort of HSAN V heterozygous human carriers. Surprisingly, we found that NGF R100W/m mice, despite

A Missense Point Mutation in Nerve Growth Factor (NGFR100W) Results in Selective Peripheral Sensory Neuropathy

“…Consistent with our studies, other mutation(s) at the R100 position (NGF R100E and NGF P61SR100E ) didn't affect NGF binding to TrkA, while it abolished NGF binding to p75 NTR (Capsoni et al, 2011;Covaceuszach et al, 2010). Together, these provide strong support a role of p75 NTR in NGFinduced pain function and failure to activate p75 NTR signaling is likely the cause for loss of pain in HSAN V patients (Capsoni, 2014;Capsoni et al, 2011;Cattaneo and Capsoni, 2019;Sung et al, 2018;Sung et al, 2019;Testa et al, 2019;Testa et al, 2018;Yang et al, 2018). HSAN V is an extremely rare disease that makes it almost impossible to perform systematic study of NGF R100W in terms of its mechanism and function in vivo.…”

“…Interestingly, unlike HSAN IV patients with recessive TrkA mutation(s) that develop pain insensitivity as well as mental retardation, HSAN V patients suffer from selective loss of pain sensation with normal cognitive function, suggesting that the NGF R100W mutation causes selective loss of pain function, but likely with intact trophic function (Einarsdottir et al, 2004;Minde et al, 2009;Minde et al, 2004b;Minde, 2006;Perini et al, 2016;Sagafos et al, 2016). Therefore, this NGF R100W mutant can provide an important tool to uncouple the trophic function of NGF from its nociceptive actions (Capsoni, 2014;Capsoni et al, 2011;Cattaneo and Capsoni, 2019;Sung et al, 2018;Sung et al, 2019;Testa et al, 2019;Testa et al, 2018;Yang et al, 2018).…”

“…HSAN V is an extremely rare disease that makes it almost impossible to perform systematic study of NGF R100W in terms of its mechanism and function in vivo. Given that NGF is highly conserved between mice and human, mouse models of HSAN V carrying NGF R100W provide an important vehicle to carefully examine the effects of NGF R100W on development/ maintenance of CNS and PNS in vivo (Testa et al, 2019;Testa et al, 2018;Yang et al, 2018).…”

Developing Modern Pain Therapies

“…These antibodies can show considerable efficacy however, they are also associated with side effects. In particular, NGF neutralization can trigger neuropathy through a loss of trophic support (Einarsdottir et al, 2004;Testa et al, 2018). Moreover, a complete loss of pain perception is not necessarily helpful and treatment with anti-NGF medications can cause an increase in osteoarthritis pathology that caused an initial halting of anti-NGF therapies (Lane et al, 2010).…”