Pain is a universal mark of disease, a major reason to seek medical evaluation, and a huge burden in physical and emotional suffering, morbidity, direct costs for health care and drugs, and in indirect costs of missed work and commitments. Dr. Mulvihill's long-time engagement with a large family with a likely autosomal dominant periodic pain syndrome (PPS) provides a research resource for the proposed doctoral project. The severely affected now 31-year-old proband is known NOT to have a porphyria, familial Mediterrean fever, periodic Hiberian fever, or Fabry disease. 20 other blood relatives in 4 generations are reported to be affected by several family members. The null hypothesis is that no gene responsible for PPS can be identified in this family. The alternate hypothesis and expected outcome will be that we will identify a PPS gene. A total of 11 informative matings give a estimated power of 99%, 95%, and 88% for LOD scores of 1, 2 and 3, respectively for detecting linkage under the proposed genome-wide genotyping procedures and standard assumptions. The broad and long-term objective of the study is to map and characterize the family's causative mutation in the putative underlying single gene, with the careful and mentored application of modern molecular and statistical genetic techniques. Further work on the pathogenetic role of the gene will improve understanding of other genetic determinants of pain and perhaps even suggest a novel therapeutic agent with wider usefulness than in just one rare mendelian family.
The specific aim i s to identify and characterize the chromosomal region of a putative single gene locus for a newly described periodic pain syndrome (PPS) through linkage analysis and mutation detection in a large family. Classic family genetic linkage study design will take advantage of state-of-the-art genotyping by microarray single nucleotide polymorphisms, supplemented, if needed, by fine mapping with markers from the International HapMap Project. This strategy will require scrupulous delineation, characterization, and verification of the clinical phenotype through in person clinical studies and record retrieval. Genome-wide scanning, linkage analysis, and direct sequencing will detect a causative mutation.
In the past half-century, in-depth understanding of rare diseases caused by changes in single genes has led to improved diagnosis, new therapies, and improved care for patients with common diseases. Pain is frequent in many illnesses and a common reason for medical care. A family with periodic pain that seems to be a newly recognized disease will be studied to find the culprit gene and apply the findings to more common conditions.
