Family with Two Rare Syndromes Reveals Immunity Glitch

Members of a three-generation family in France who suffer from widespread infections and fragile skin, joints, bones, and blood vessels share an underlying and unexpected immune system glitch, according to a new report in Science Immunology.

The grandmother died of septic shock at age 76. She had the same collection of problems that plague her 45-year-old daughter, and her 19-year-old granddaughter. They have two syndromes that aren’t known to occur together:

• “Chronic mucocutaneous candidiasis” brings persistent infections with the yeast Candida albicans, in the vagina, skin folds, mouth (thrush), and other mucosal linings. All three women also suffer UTIs, ear-nose-and-throat infections, and bacterial skin infections.
• Connective tissue disorders similar to Ehlers-Danlos syndrome include hypermobile joints; soft, velvety, super-stretchy skin; palm and sole blisters; stretch marks; slow wound healing; poor digestion; osteoporosis; and, most debilitating, chronic widespread pain. Abnormal connective tissue is dangerous, because blood vessels and organs such as the uterus and intestines can burst.

Yet other symptoms include frequent migraines, fatigue, insomnia, Reynaud’s phenomenon, tumors, and retained baby teeth.

The women treat the symptoms one-at-a-time: rounds of antibiotics, painkillers, digestive aids, skin creams, vitamin D supplements, osteoporosis drugs, and more. But what if a single mutation lay behind the spectrum of symptoms? Would identifying it reveal a single drug target that could make their lives easier – either a repurposed drug or impetus to develop a new one? Dissecting the cell-cell signaling pathways gone off course might lead to novel therapeutic approaches to either of the two arrays of symptoms, helping others.

The information on this intriguing family is part of a resource called the human gene connectome, developed at the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University. Led by Jean-Laurent Casanova and with international collaborators, the group is illuminating how single-gene mutations spotlight immune system problems. In my 2013 post “A GPS View of the Human Genome,”  team member Yuval Itan explained how the connectome works.

Narrowing Down the Data

The three women had seen enough doctors to have been tested for the best-known mutations behind connective tissue disorders. But their collagen, fibrillin, TGF-β, and SMAD genes were just fine.

So the researchers explored 23,000 or so single-DNA-base places in the protein-encoding part of the genome (the exome) where people vary. These markers are called single nucleotide variants (SNVs) or polymorphisms (SNPs). Because the combination of symptoms was so rare, the investigators sought uncommon SNVs.

After eliminating variants that came up in several databases, about 400 remained that alter a gene in a way that changes the amino acid sequence of the encoded protein and could therefore make someone sick. The grandmom, mom, and daughter share 106 of the possibly meaningful 400 gene variants. Consulting the human gene connectome database that links immune ills with other genes narrowed the candidate genes down to 18.

Finally, one gene emerged whose function made sense: MAPK8. The small family had their own, “private” mutation in a splice site – that’s a part of a gene that controls how pieces of it are accessed to sculpt the final protein product.

Untangling Strangled Signals

To get to the bottom of what was going wrong, the investigation moved to fibroblast cells sampled from the women’s skin, to observe the cell-signaling pathway that the protein that MAPK8 encodes controls. The protein, “JNK1” (for c-Jun-N-terminal kinase 1), is an enzyme that affects response to stress and plays a role in T cell development and avoiding cell death.

In the family’s cells, JNK1 can’t make IL-17 as it normally would. IL-17 is an immune system biochemical, an interleukin, which promotes the inflammatory response to injury or infection.

Helper T cells normally make IL-17, which normally sends other white blood cells (neutrophils and macrophages) to infection sites, where they fight the bacteria and mop up debris, respectively. The study of the small family revealed that lack of IL-17 might also ease infection by the yeast Candida albicans.

But there was more. The IL-17-deficient fibroblasts also couldn’t lay down collagen and elastin proteins to build connective tissue. Specifically, the IL-17 couldn’t recognize TGF-β signaling.

So there’s a single glitch: a block in helper T cells’ release of IL-17 blocks the assembly of connective tissue, while also opening up the body to rampant yeast infections.

JNK1, like other kinases, has been a drug target for cancer, neurodegenerative conditions, and immune dysfunctions for decades. The new work suggests new therapeutic directions.

A More Nuanced View of Human Genomes

The researchers call the family from France an “experiment of nature.” A more accurate cliché might be “chance favors the prepared mind,” for narrowing down a single source of a connective tissue disorder and out-of-control yeast infections wasn’t obvious. The human gene connectome made it possible. And as more human genomes are analyzed and compared, more odd collections of symptoms will be traced to their genetic origins.

I’ve long been more interested in the mutational underpinnings of sets of symptoms than in the data dumps of massive DNA sequencing studies. It’s a little like comparing a detailed map of the United States (a genome) to delving into the histories of two towns (the two sets of symptoms in the family). And just as the residents of two towns may be ultimately traced to the same original settlers, so too can clever investigators narrow down the gene variants that explain seemingly separate syndromes.

Thank you to the researchers for providing the images from their paper.