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.