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Exome Sequencing Links Point Mutation to Family's Insensitivity to Pain

NEW YORK (GenomeWeb) – Researchers have traced a rare pain insensitivity disorder affecting one family to a single point mutation.

By studying people who don't experience pain or experience it differently than most people, the researchers hope to tease out possible drug targets to treat people who suffer from chronic pain, a condition affecting more than 11 percent of adults in the US.

Members of the Italian family in this new study have broken bones or burned themselves without feeling any pain, despite possessing the usual complement of nerves. By sequencing the exomes of family members, researchers led by University College London's James Cox uncovered a point mutation in the ZFHX2 gene among affected family members, as they reported yesterday in the journal Brain. In mice, this mutation also leads to decreased pain sensitivity.

"We're working to gain a better understanding of exactly why they don't feel much pain, to see if that could help us find new pain relief treatments," Cox said in a statement.

Studies of other families with recessive forms of congenital insensitivity to pain have previously linked mutations in PRDM12 to alterations in pain perception.

Since childhood, six members from three generations of this family have exhibited hypoalgesia. In addition to pain insensitivity, the affected family members rarely, if ever, sweat. And, although they show variable sensitivity to heat and cold, some members can withstand extreme temperatures. They also have low sensitivity to capsaicin, a component of chili peppers.

Hypoalgesia within the family appears to be autosomal dominantly inherited, Cox and his colleagues added. However, they noted that affected family members did feel some pain, such as headaches, back pain, and during childbirth, and could feel innocuous light touches.

Using blood samples obtained from family members, the researchers sequenced their exomes. After filtering and Sanger sequencing verification, Cox and his colleagues uncovered two novel coding variants that segregated with affected family members. As one variant, in SUPT3H, was marked as benign by two pathogenicity prediction tools and isn't suspected to alter splicing, the researchers focused on the second variant, a point mutation in ZFHX2. This variant was predicted by those same two tools to be deleterious and was absent from public SNP databases.

ZFHX2 encodes a large, 2,572 amino-acid protein containing 17 zinc-finger motifs and three homeodomains. The mutation is located in one of the homeodomains and changes a highly conserved arginine to lysine.

Global knockout ZFHX2 mice similarly have low pain sensitivity, as compared to their wild-type littermates, the researchers reported. In mice, the ZFHX2 gene is highly expressed in the dorsal root ganglion, which relays pain signals. Additionally, the researchers generated transgenic mice with the orthologous amino acid in ZFHX2 mutated, and found that they also had lower sensitivity to high heat and capascin.

As ZFHX2 is suspected to be a transcriptional regulator, Cox and his colleagues traced the effects of the mutation on other genes in mice. Sixteen genes were downregulated in mutant dorsal root ganglia, as compared to controls, and these genes included ones like GAL, SST, and PTGIR that have previously been linked to pain signaling. A further analysis of these genes found that they harbored four common AG-rich DNA sequence motifs. A Gene Ontology analysis found this motif to be enriched among gene families involved in signal sensitizing nociceptors.

This suggested to the researchers that ZFHX2 is key part of normal pain perception.

"With more research to understand exactly how the mutation impacts pain sensitivity, and to see what other genes might be involved, we could identify novel targets for drug development," added co-author Anna Maria Aloisi from the University of Siena.