NIH researchers discover gene alteration in rare autoinflammatory disease

By Raymond MacDougall
Associate Director of Communications, Division of Intramural Research

Researchers use a molecular structure model of PLCG2 to depict the substitution of DNA in the rare disorder APLAID. The small blue element at the top-left of the structure on the left is substituted for the small red element shown in the PLCG2 structure model on the right.
Just 10 months after publishing a new disease discovery, researchers from the National Institutes of Health have repeated the achievement, bringing their attention back to the same gene. Both diseases cause ultra-rare autoinflammatory conditions, but because the gene is altered in different ways in each disorder, they present distinct symptoms. The team includes researchers studying inflammatory diseases at the National Human Genome Research Institute (NHGRI) and collaborators at the Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases.

The newly identified rare condition is caused by an alteration in the gene that encodes phospholipase C-gamma2 (PLCG2), an enzyme involved in the regulation of immune cells as well as inflammation and immune responses. Instead of a deletion of DNA sequence that characterized the earlier disease discovery, the new condition is caused by a substitution of DNA in an exon of the gene. Exons are sub-parts of DNA sequence within a gene that carry the code for proteins. The alternate DNA sequence modifies the function of the enzyme. Researchers found the gene through whole-exome sequencing, a technique that focuses on the 1 to 2 percent of the human genome that code for proteins.

Their report appeared in the Oct. 5, 2012, issue of the American Journal of Human Genetics. The earlier report appeared in the Jan. 11, 2012, issue of the New England Journal of Medicine.

"Advanced techniques in genetic analysis have enabled us to identify the causes of a number of autoinflammatory diseases and to recognize that they are not one large group," said Ivona Aksentijevich, senior author and staff scientist in NHGRI's Medical Genetics Branch. "We expect that a better understanding of such conditions will ultimately help with development of more targeted therapies."

The researchers discovered the distinct condition with remarkably few cases. A father and daughter are the only affected patients in this study. Each participated for more than 10 years, along with four unaffected family members, in an NIH clinical study directed by Daniel Kastner, M.D., Ph.D., co-author and NHGRI scientific director. Their symptoms include recurring blisters, joint pain, bronchial infection, eye and colon inflammation and mild immunodeficiency. Until now, Dr. Kastner's clinical research team at NIH was unable to diagnose what caused the father and daughter's symptoms. Each of the patients exhibited a range of the symptoms that failed to respond to most conventional therapies.

The NHGRI team has studied genetics of inflammatory disorders for 20 years, even establishing the concept of autoinflammatory diseases. This class of diseases is caused by variants in one or more genes regulating innate immune responses, a type of immunity distinct from that acquired by prior exposure to pathogens. People with autoinflammatory diseases suffer from lifelong recurrent episodes of systemic inflammation. Although disease-causing variants &mdash: versions of the genes with function-changing alterations — are identified in 12 genes responsible for various single-gene autoinflammatory diseases, more than 50 percent of patients with autoinflammatory symptoms are still undiagnosed.

The researchers call the new disorder APLAID, which is an abbreviation of the descriptive name, autoinflammation, PLCG2-associated antibody deficiency and immune dysregulation. They used part of the name in their earlier disease discovery, calling that condition PLAID. The DNA sequence substitution in APLAID leads to more pronounced symptoms of autoinflammation than experience by patients with PLAID. The most remarkable, among many physical distinctions, is that symptoms of PLAID are triggered by the cold unlike the symptoms of APLAID.

"Different alterations in the same gene may exhibit very different effects," said Qing Zhou, Ph.D., a co-author and postdoctoral fellow in NHGRI's Inflammatory Diseases Section. She noted that research on people with different alterations in PLCG2 shows the wide variability that can occur with mutations within a gene, especially differences in cell signaling that likely are tied to a broad range of diseases of the innate immune system. The group continues research into the role in inflammation of PLCG2 as well as to discover genetic causes in patients with other autoinflammatory diseases.

Posted: October 31, 2012

Last updated: October 31, 2012