Document Type

Dissertation

Date of Degree

Fall 2016

Access Restrictions

Access restricted until 02/23/2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Alexander G. Bassuk

Abstract

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases, the genetic basis is unknown. Via whole-exome sequencing and linkage analysis, we determined the most likely causative mutations in four families. While the mutations are in three different genes – FBLIM1, PLCG2 and PIP; all three genes are involved in Fcγ signaling and osteoclast activation.

In a large cohort of 61 individuals with CRMO, we performed gene and pathway based association analysis using the 1000 genomes participants of European ancestry as controls. One gene from the family-based analyses, ANO6, was significantly enriched for rare variants in our cohort of cases. ANO6 is involved in P2RX7- mediated inflammasome activation and in the regulation of bone mineralization. While no pathways were enriched for rare variants in the CRMO cohort after genome-wide correction, four pathways were significantly enriched for rare variants in the control samples, indicating a protective effect of the variants. The second most significant pathway, activation of chaperone genes by XBP1s, is relevant to CRMO pathogenesis as XBP1s is a transcription factor that attenuates ER stress, and regulates the expression of genes involved in RANKL signaling and bone remodeling.

An association analysis using a larger set of cases followed by functional validation of candidate genes is necessary to confidently declare the mutations isolated in the work presented here to be pathogenic. Our preliminary findings suggest that mutations in genes involved in both the inflammatory response and bone remodeling underlie the pathogenesis of CRMO.

Keywords

bone, inflammation, whole exome sequencing

Pages

x, 132

Bibliography

119-132

Comments

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Copyright

Copyright © 2016 Allison Jeanne Cox

Available for download on Saturday, February 23, 2019

Included in

Genetics Commons

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