NEW YORK (GenomeWeb) – With the help of exome sequencing, researchers have defined the genetic cause of a rare, monogenic intestinal disease that is marked by serious gastrointestinal problems and other complications that include deep vein clots.
A team led by the National Institute of Allergy and Infectious Diseases focused on 10 individuals from Turkey and one from the Netherlands who had symptoms ranging from abdominal pain and diarrhea to inflamed bowels or recurrent infections, apparently related to their propensity for protein loss from the blood to the gut, related swelling, inappropriate lymph node dilations, and poor nutrient absorption.
As they reported yesterday in the New England Journal of Medicine, the researchers used exome or targeted gene sequences from affected individuals and their family members to narrow in on mutations altering both copies of CD55, a gene regulating the complement arm of the immune system. These homozygous mutations appeared to interfere with the CD55 protein's ability to staunch complement system activity, leading to a rise in levels of the complement player C5a and rampant immune activity against the body's own tissues such as the digestive tract blood and lymph vessels.
The condition was dubbed CHAPLE syndrome (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy).
"People with CHAPLE disease lack CD55 protein and, with it, the ability to control complement activity," senior author Michael Lenardo, chief of the molecular development of the immune system section at the NIAID immunology lab, said in a statement. "The question is whether treating people with a substitute for CD55's activity can help slow or reverse the symptoms of this disease."
For their analyses, Lenardo and colleagues brought together 11 CHAPLE cases occurring in eight consanguineous families. They also considered two deceased family members with similar symptoms — characterized by so-called protein-losing enteropathy features such as gastrointestinal problems, edema, and malnutrition.
After sequencing protein-coding portions or single genes in patient and family member genomes at the NIAID or at the Ludwig Boltzmann Institute for Rare and Undiagnosed Disease in Vienna, the team identified homozygous CD55 loss-of-function mutations in affected individuals. On the other hand, family members with alterations affecting only one copy of the gene did not have CHAPLE symptoms, pointing to recessive inheritance of the condition.
The researchers noted that the CD55 mutations found in the families were missing from the Exome Aggregation Consortium database, and other loss-of-function mutations in the gene were present in just 53 individuals from the 60,000 or so individuals in ExAC. Similarly, moderately deleterious mutations turned up in just one person when they screened another 239 individuals from Turkey.
When the team tested more individuals with CHAPLE-like symptoms, though, it found half a dozen more individuals with loss-of-function changes affecting both copies of CD55.
From these findings — and results from experiments with cell lines showing diminished CD55 activity — the researchers speculated that interfering with complement activity might also dampen features of CHAPLE syndrome.
Indeed, when they tested the complement-inhibiting antibody eculizumab in cells from individuals with CHAPLE syndrome, the complement immune system activity dipped, prompting speculation that this treatment might also benefit individuals with the disease.