NEW YORK (GenomeWeb) – A Baylor College of Medicine-led team found a handful of germline mutations in the signaling pathway gene TRAF7 that seem to contribute to a mysterious multisystem disorder marked by symptoms such as developmental delays, congenital heart defects, dysmorphia, and unusual development of limbs, fingers, and toes.
Using clinical exome sequence data generated at Baylor, the researchers searched for mutation culprits in seven unrelated individuals with shared symptoms related to this condition, uncovering several mutations in TRAF7 on chromosome 16 — variants they subsequently linked to lower-than-usual ERK1/2 pathway activity through a series of functional assays. The results appeared online yesterday in the American Journal of Human Genetics.
Although TRAF7 had not been implicated in conditions related to the multisystem condition in the past, the team noted, alterations in the gene and other members of the ERK1/2 pathway have been proposed as contributors to everything from RASopathies to some forms of cancer.
"[P]revious work has shown that a change of function of the ERK1/2 pathway … is associated with a group of diseases called RASopathy, which share some features with the TRAF7-related disorders reported in this work," co-senior author Xia Wang, a molecular and human genetics researcher at Baylor College of Medicine and Baylor Genetics assistant laboratory director, said in a statement. "Other works indicate that mutations in TRAF7 also have been seen in cancer tissue."
The researchers analyzed clinical exome sequence data from seven individuals with characteristic symptoms of the multisystem condition — from motor, speech, and other developmental delays to heart, limb, and facial changes. The group included individuals as young as a week old and as old as 43.
All seven of the patients — five males and two females — carried TRAF7 alterations, with mutations in all but one of the individuals occurring de novo, the team reported. One of the variants was shared by four of the affected individuals, while three others occurred in one person apiece. But none of those suspicious variants turned up in a search of the ExAC or gnomAD sequence databases.
When the researchers explored the functional effects of the disease-related variants using site-directed mutagenesis, knockdown, cell line, mouse model, and other experiments, they saw ties between the TRAF7 mutations and signaling through the ERK1/2, or MAP kinase, pathway. In mice with reduced levels of ERK1 or ERK2, for example, they detected heart, limb, and craniofacial abnormalities, along with central nervous system and behavioral changes.
"Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development," the authors wrote.
The team noted that additional research is required to more fully explore the range of phenotypes associated with TRAF7 mutations, along with the apparent ties to cancer, which was diagnosed in at least one of the seven individuals included in the current study.
"One of the oldest patients in our cohort did have a meningioma," Wang said. "TRAF7 joins the growing list of genes that are implicated in both cancer and human developmental disorders."