Investigation into the Molecular Biology of Human Genetic Sensory Disorders of Painlessness and Itch

Pain and itch are two distinct unpleasant sensations. Despite having different characteristics, both pain and itch are often disabling, particularly when those sensations persist and result in a chronic condition. Considerable research has been focused on exploring alternative treatment for chronic pain, one of which is the research of painlessness mechanism. Congenital insensitivity to pain (CIP) is a genetic sensory disorder in which the individuals are painless since birth. Various genes have been identified to be associated with CIP, but there are also several painlessness cases that remain unsolved. The author discovered a novel mutation in *CMAS* in three unrelated families with CIP phenotypes, hence supporting *CMAS* as a strong candidate gene causing congenital insensitivity to pain. This work aims to explore the role of *CMAS* in pain pathways and the mechanism linking *CMAS* c.92C>T mutation to painless phenotypes. However, the novel p.Ser31Phe mutation in the N-terminus of CMAS did not affect normal nuclear localisation nor the enzymatic function of the protein in sialylation. There were not any significant hits of interacting proteins found from the proteomic study. An interesting finding consistent with previous studies of CMAS is the fact that this protein tends to precipitate, potentially associated with the N-terminal of human CMAS that is suggested to destabilise the protein. The protein is also prone to cleavage, particularly in its N-terminus. Further studies are needed to investigate the mechanisms linking *CMAS* mutation with painlessness, including generating mouse models carrying the mutation. Another gene investigated by the author in this study is the *PRDM12*. Mutations in *PRDM12* have been known to be associated with CIP, including the polyalanine tract expansion mutation to 19 alanine repeats. Interestingly, expansion mutation of the same gene to 18 alanines result in a completely different phenotype, an intense itch condition referred to as midface toddler excoriation syndrome (MiTES). In this study, the author investigated the genotype-phenotype correlation of *PRDM12*-MiTES, confirming its diagnostic criteria. This study also confirms that polyalanine tract expansion in *PRDM12* in both MiTES and CIP results in aggregation events. Protein aggregates possibly deviate normal functions of PRDM12, including that in the development of nociceptors, causing sensory disorders in the form of either painlessness or chronic itch.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Pamela, Yunisa

Advisor dc:contributor.advisor

• Woods, Christopher

• Congenital insensitivity to pain
• Genetics
• Itch
• Painlessness
• Sensory

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e1b4a22b-9918-4c6d-8b1c-671b5cfc868f/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.108087

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/367529