Researchers at Children's Hospital Boston, who specialize in studying the genetics of rare eye-movement disorders, have found a rare genetic syndrome whose implications go far beyond the eye, raising intriguing questions about human cardiovascular and brain development.
The syndrome involves a mutation to HOXA1, a gene that has been extensively studied in mice, but about which little is known in humans. HOXA1 belongs to a large family of HOX genes that govern very early embryonic development and the making of the body plan. HOXA1 is the first HOX gene turned on in mice, and presumably in the human body, and is involved in patterning of the growth of the head, face, and brainstem.
Mice that lack both copies of HOXA1 universally die. Until this study, no human HOXA1 mutation had ever been identified, and it was assumed that complete loss of HOXA1 function would be lethal. But the Children's investigators, led by graduate student Max Tischfield and neurologist Dr. Elizabeth Engle of the Children's Hospital Boston Program in Genomics and the Harvard Medical School Program in Neuroscience, have found living people with two mutated copies of HOXA1 -- from three different parts of the world.
"This is the first description of a human syndrome resulting from any of the HOX genes involved in brain development, and the first report of a total loss of any HOX gene in humans," says Engle, senior author of the study.
Tischfield and Engle had been studying genetic disorders that interfere with peoples' ability to move their eyes horizontally (left or right). Collaborators in Saudi Arabia alerted them to patients they'd been seeing who had not only restricted horizontal eye movement, but also deafness and motor impairments. The Saudi clinicians began to carefully reexamine their patients, while Tischfield and Engle looked at the patients' DNA to try to identify a causative gene.
All 9 patients with the syndrome (dubbed Bosley-Salih-Alorainy syndrome, or BSAS, after the Saudi discoverers) had horizontal gaze abnormalities. Eight were profoundly deaf, 3 had external ear defects, 7 had delayed motor development, and 2 met criteria for autism spectrum disorder with cognitive and behavioral impairment. In addition, 7 had malformations or complete absence of one or both internal carotid arteries, one of the two carotid arteries that are the main suppliers of blood to the brain.
DNA linkage studies and follow-up analyses all implicated HOXA1 in the syndrome. But to make the case, Tischfield and Engle needed to find HOXA1 mutations in other populations. For over a decade, Engle has been collecting large pedigrees of families with eye-movement disorders. She and Tischfield tapped this database and found a child from Turkey whose symptoms were much like those of the Saudi patients. This child also had a HOXA1 mutation, but in a different location on the gene.
Fortuitously, Engle and Tischfield also recalled a paper reporting a syndrome in 10 Native American children in Arizona that had many similarities to BSAS. They obtained these children's DNA and found that they also had a HOXA1 mutation, at yet another location on the gene. Like the people with BSAS, the children had horizontal gaze restriction, deafness, and delayed motor development, and some had loss or malformation of the carotid arteries. However, all also had breathing difficulties and mental retardation, and some had facial weakness, paralysis of the vocal cords and heart defects of a type that occur very early in embryonic development. The researchers attribute the differences between the Middle Eastern and Native American patients to environmental influences and the influence of other gene variations unique to each group.
Overall, however, the findings suggest that HOXA1 is involved in early development of the cardiovascular system, a function of the gene not previously known. "The cardiovascular malformations in people with HOXA1 mutations were never reported in mice," says Tischfield, the study's first author. "We've potentially uncovered a new developmental role for HOXA1 in vascular patterning in humans, a role that may have been overlooked in mice."
Most intriguingly, the association of both mental retardation and autism with HOXA1 mutations suggests that early malformation of the brainstem, which controls "lower" functions such as eye movement and breathing, may also lead to impairment in higher cognitive and behavioral function.
"HOXA1 is expressed in the brainstem, but we do not believe it is expressed in the higher brain (the cerebrum or cerebellum)," Tischfield notes. "But there's a lot of output from the brainstem during brain development. Serotonin comes from the brainstem, and many people believe that autism and mental retardation result from an abnormal influence of serotonin. Our paper may spark ongoing interest in how serotonin systems modulate development of the higher brain."
Interestingly, in utero exposure to thalidomide very early in pregnancy, during the time when HOXA1 is turned on, causes damage in the brainstem that mimics the HOXA1 syndrome. In addition, a previous autopsy of an autistic individual showed brainstem pathology similar to that of mice whose HOXA1 genes had been deleted.
"HOXA1 is a gene that's been looking for a disorder for a long time," says Engle. "It's one of a series of interesting genes we've stumbled on by using complex eye-movement disorders as a marker for developmental defects."