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Family Sequencing Study Reveals Ties Between Pain Perception, Histone Regulatory Gene

NEW YORK (GenomeWeb) – An international team led by investigators in the UK and Germany has uncovered alterations in the PRDM12 gene that appeared to affect individuals' ability to perceive pain.

As they reported online yesterday in Nature Genetics, the researchers used a combination of array-based mapping, exome sequencing, and targeted sequencing to search for mutations associated with pain perception in individuals from 11 families affected by recessive forms of congenital insensitivity to pain (CIP).

The search uncovered ties between CIP and 10 different homozygous mutations in PRDM12 — a gene that the team focused on for its follow-up functional studies of sensory neuron development.

Together, results in mouse embryos, Xenopus embryos, and cell lines suggested that glitches in the gene alter epigenetic processes that contribute to developing sensory neurons called nociceptors, leading to lifelong problems in perceiving pain.

"Our data imply that the pathological mechanism involves a loss of control of histone modification during critical points in nociceptor genesis," the study's authors wrote, noting that the "histone-modifying activity of PRDM12 suggests a possible target for new methods of pain relief through reprogramming of the overactive nociceptors."

Chronic or excessive pain is a well-recognized burden for some individuals, their families, and society, the team explained, a problem that's exacerbated by our limited ability to treat pain.

At the other end of the spectrum, though, pain-free life is also difficult. Individuals with pain perception problems such as CIP suffer from frequent injuries that can lead to mutilated fingers, toes, tongues, and other forms of tissue damage.

In the hopes of better understanding one extreme (pain perception problems) to treat the other (difficult-to-treat pain), authors of the study started by looking at two families with autosomal recessive forms of CIP.

The team started with SNP-based testing on one of two families with autosomal recessive CIP. The selected family contained consanguineous relationship, making it possible to narrow in on a CIP-related region on chromosome 9 by autozygosity mapping.

When they did exome and/or targeted sequencing on affected representatives from both families and from two more families with genetically unclassified CIP, the researchers tracked distinct mutations affecting both copies of PRDM12 in affected individuals from each family.

Meanwhile, in a subsequent screen for PRDM12 mutations in 158 individuals with sporadic CIP or CIP that appeared to be inherited in an autosomal recessive manner, the team saw seven more individuals with homozygous glitches in PRDM12.

All told, the search uncovered 10 different homozygous mutations to the gene, including several missense mutations, a splice site mutation, and one alteration involving a run of 18 alanine bases.

Through a series of functional follow-up experiments on developing mouse or Xenopus embryos — together with experiments done on a monkey cell line, human embryonic stem cells, and induced pluripotent stem cells — the team saw evidence that PRDM12 typically functions as an epigenetic regulator that modifies histones during sensory neuron development. 

In the presence of PRDM12 mutations similar to those detected in individuals with CIP, on the other hand, the researchers noted that this aspect of sensory system development diminishes, leading to a loss of pain perception.

Based on these findings, those involved in the study speculated that it may be possible to tap into such pathways both to understand conditions such as CIP and develop strategies for treating individuals who experience high pain levels and/or long-lingering pain.