Otulipenia is characterized by abnormal inflammation throughout the body. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, the uncontrolled inflammation that occurs in otulipenia can damage many of the body's tissues and organs, including the gastrointestinal system, joints, and skin. Disorders such as otulipenia that result from abnormally increased inflammation are known as autoinflammatory diseases.

Signs and symptoms of otulipenia usually begin within the first few weeks of life, with recurring episodes of fever; diarrhea; painful, swollen joints; and skin rashes. The skin rashes are due to inflammation of the layer of fatty tissue under the skin (panniculitis), which causes painful red bumps. Some people with otulipenia have an abnormal distribution of fatty tissue in their bodies (lipodystrophy). Affected infants have difficulty growing and gaining weight at the expected rate (failure to thrive). Damage to the body's tissues and organs caused by inflammation is life-threatening if the condition is not treated.

The prevalence of otulipenia is not known. At least four cases have been reported in the medical literature.

Otulipenia is caused by mutations in the OTULIN gene. The protein produced from this gene helps control inflammation. Inflammation can be turned on by a cellular process called ubiquitination, in which molecules called ubiquitin are attached to certain proteins. In particular, signaling pathways that lead to inflammation are stimulated by the attachment of chains of ubiquitin molecules linked end-to-end (linear ubiquitin chains). The OTULIN protein helps control inflammation by removing these linear ubiquitin chains.

OTULIN gene mutations that cause otulipenia lead to production of an OTULIN protein with reduced function. As a result, removal of linear ubiquitin chains is impaired, and signaling pathways that cause inflammation are abnormally active. The excessive inflammation that results causes fever, diarrhea, panniculitis, and the other signs and symptoms of otulipenia.

Normal Function

The OTULIN gene provides instructions for making a protein that helps regulate inflammation, which is part of the body's early immune response to foreign invaders. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight the invaders and facilitate tissue repair. Inflammation can be turned on by a cellular process called ubiquitination, in which molecules called ubiquitin are attached to certain proteins. When foreign invaders are recognized, chains of ubiquitin molecules linked end-to-end, called linear ubiquitin chains, are attached to particular proteins. The addition of these chains stimulates signaling pathways that result in inflammation. Once the infection is under control, the body stops the inflammatory response to prevent damage to its own cells and tissues. The OTULIN protein helps control inflammation by removing linear ubiquitin chains.

In addition to inflammation, the OTULIN protein is thought to be involved in regulating development before birth and controlling cell death. Researchers are working to understand the protein's role in these processes.

Health Conditions Related to Genetic Changes

Otulipenia

At least three mutations in the OTULIN gene have been found to cause otulipenia, a condition that causes abnormal inflammation in the body, beginning in infancy. Affected babies have recurrent episodes of fever, diarrhea, painful joints, and skin rashes. The gene mutations involved in otulipenia reduce the function of the OTULIN protein. As a result, removal of linear ubiquitin chains is impaired, and signaling pathways that cause inflammation are abnormally active. The excessive inflammation that results causes the signs and symptoms of otulipenia and damages organs in the body; it can be life-threatening if not treated.

Other Names for This Gene

• AIPDS
• deubiquitinating enzyme otulin
• FAM105B
• family with sequence similarity 105, member B
• FLJ34884
• GUM
• OTU domain-containing deubiquitinase with linear linkage specificity
• ubiquitin thioesterase Gumby
• ubiquitin thioesterase otulin

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.