Hereditary Sensory Polyneuropathy, Pain Insensitivity and Global Developmental Delay due to Novel Mutation in PRDM12 Gene

PRDM12 Is Transcriptionally Active and Required for Nociceptor Function Throughout Life

“…Subsequently, we confirmed that the variant segregated with the disease in a recessive fashion: in a homozygous state in patients 1 and 2 and in a heterozygous state in each of the four parents ( Figure 1B ). A different homozygous variant in the same position (c.224-2A>G) has previously been published in a patient suffering from CIP accompanied with global developmental delay, similarly to the patients we describe (Saini et al, 2017 ). Subsequent filtering of the WES failed to detect any additional rare, high CADD-PHRED scoring variants within the other known CIP genes, including NGF, NTRK1, SCN9A, SCN11A, ZFHX2, FAAHP1 , and CLTCL1 .…”

“…The analysis of WES of patient 1 identified eight rare variants in genes associated with autism and/or ID, but these are not shared with patient 2 and are unlikely to explain the CNS symptoms in this family. Interestingly, a splice-site acceptor variant reported here is in the same position as an already reported PRDM12-CIP case of different ethnic background, presenting with typical CIP symptoms including ID (Saini et al, 2017 ). Why should variants at this position but not in others have an impact on CNS function is not clear.…”

Loss of Prdm12 during development, but not in mature nociceptors, causes defects in pain sensation

“…Recently, additional mutations have been identified that cause CIP (Imhof et al, 2020;Nahorski et al, 2015), including those of the transcription factor PRDM12 (PRDI-BF1-RIZ homologous domaincontaining family) (Chen et al, 2015). As in other forms of CIP, patients with Prdm12-associated CIP are unable to feel pain from noxious chemical, thermal, or mechanical stimuli but retain normal touch, proprioception, and tickle sensations (Chen et al, 2015;Saini et al, 2017;Zhang et al, 2016). Therefore, similar to how drugs have been developed that target NGF and Nav1.7, Prdm12 or its downstream effectors may serve as potential novel analgesic targets (Hoffman et al, 2011).…”

Loss ofPrdm12during development, but not in mature nociceptors, causes defects in pain sensation

“…More recently, additional mutations have been identified to cause CIP (Nahorski et al, 2015), including those of the transcription factor PRDM12 (PRDI-BF1-RIZ homologous domain-containing family) (Chen et al, 2015). As in other forms of CIP, patients with Prdm12-associated CIP are unable to feel pain due to noxious chemical, thermal, or mechanical stimuli, but retain normal touch, proprioception, and tickle sensations (Chen et al, 2015;Saini et al, 2017;Zhang et al, 2016). Therefore, Prdm12 or its downstream effectors may serve as potential novel analgesic targets similar to drugs that have been developed targeting other genes underlying CIP, NGF and Nav1.7 (Hoffman et al, 2011).…”