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Rare Eye-movement Disorder May Shed Light On Brain And Cardiovascular Development

September 12, 2005
Children's Hospital Boston
Researchers have identified a rare genetic syndrome affecting eye movement -- affecting three distinct populations -- that raises intriguing questions about early cardiovascular and brain development. The syndrome affects a gene involved in very early embryonic development that has been extensively studied in mice, but about which little has been known in humans.

Researchers at Children's Hospital Boston, who specialize in studyingthe genetics of rare eye-movement disorders, have found a rare geneticsyndrome whose implications go far beyond the eye, raising intriguingquestions about human cardiovascular and brain development.

The syndrome involves a mutation to HOXA1, a gene that has beenextensively studied in mice, but about which little is known in humans.HOXA1 belongs to a large family of HOX genes that govern very earlyembryonic development and the making of the body plan. HOXA1 is thefirst HOX gene turned on in mice, and presumably in the human body, andis involved in patterning of the growth of the head, face, andbrainstem.

Mice that lack both copies of HOXA1 universally die. Untilthis study, no human HOXA1 mutation had ever been identified, and itwas assumed that complete loss of HOXA1 function would be lethal. Butthe Children's investigators, led by graduate student Max Tischfieldand neurologist Dr. Elizabeth Engle of the Children's Hospital BostonProgram in Genomics and the Harvard Medical School Program inNeuroscience, 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 resultingfrom any of the HOX genes involved in brain development, and the firstreport of a total loss of any HOX gene in humans," says Engle, seniorauthor of the study.

Tischfield and Engle had been studying genetic disorders thatinterfere with peoples' ability to move their eyes horizontally (leftor right). Collaborators in Saudi Arabia alerted them to patientsthey'd been seeing who had not only restricted horizontal eye movement,but also deafness and motor impairments. The Saudi clinicians began tocarefully reexamine their patients, while Tischfield and Engle lookedat the patients' DNA to try to identify a causative gene.

All 9 patients with the syndrome (dubbed Bosley-Salih-Alorainysyndrome, or BSAS, after the Saudi discoverers) had horizontal gazeabnormalities. Eight were profoundly deaf, 3 had external ear defects,7 had delayed motor development, and 2 met criteria for autism spectrumdisorder with cognitive and behavioral impairment. In addition, 7 hadmalformations or complete absence of one or both internal carotidarteries, one of the two carotid arteries that are the main suppliersof blood to the brain.

DNA linkage studies and follow-up analyses all implicated HOXA1in the syndrome. But to make the case, Tischfield and Engle needed tofind HOXA1 mutations in other populations. For over a decade, Engle hasbeen collecting large pedigrees of families with eye-movementdisorders. She and Tischfield tapped this database and found a childfrom Turkey whose symptoms were much like those of the Saudi patients.This child also had a HOXA1 mutation, but in a different location onthe gene.

Fortuitously, Engle and Tischfield also recalled a paperreporting a syndrome in 10 Native American children in Arizona that hadmany similarities to BSAS. They obtained these children's DNA and foundthat they also had a HOXA1 mutation, at yet another location on thegene. Like the people with BSAS, the children had horizontal gazerestriction, deafness, and delayed motor development, and some had lossor malformation of the carotid arteries. However, all also hadbreathing difficulties and mental retardation, and some had facialweakness, paralysis of the vocal cords and heart defects of a type thatoccur very early in embryonic development. The researchers attributethe differences between the Middle Eastern and Native American patientsto environmental influences and the influence of other gene variationsunique to each group.

Overall, however, the findings suggest that HOXA1 is involvedin early development of the cardiovascular system, a function of thegene not previously known. "The cardiovascular malformations in peoplewith HOXA1 mutations were never reported in mice," says Tischfield, thestudy's first author. "We've potentially uncovered a new developmentalrole for HOXA1 in vascular patterning in humans, a role that may havebeen overlooked in mice."

Most intriguingly, the association of both mental retardationand autism with HOXA1 mutations suggests that early malformation of thebrainstem, which controls "lower" functions such as eye movement andbreathing, may also lead to impairment in higher cognitive andbehavioral function.

"HOXA1 is expressed in the brainstem, but we do not believe itis expressed in the higher brain (the cerebrum or cerebellum),"Tischfield notes. "But there's a lot of output from the brainstemduring brain development. Serotonin comes from the brainstem, and manypeople believe that autism and mental retardation result from anabnormal influence of serotonin. Our paper may spark ongoing interestin how serotonin systems modulate development of the higher brain."

Interestingly, in utero exposure to thalidomide very early inpregnancy, during the time when HOXA1 is turned on, causes damage inthe brainstem that mimics the HOXA1 syndrome. In addition, a previousautopsy of an autistic individual showed brainstem pathology similar tothat of mice whose HOXA1 genes had been deleted.

"HOXA1 is a gene that's been looking for a disorder for a longtime," says Engle. "It's one of a series of interesting genes we'vestumbled on by using complex eye-movement disorders as a marker fordevelopmental defects."


Founded in 1869 as a 20-bed hospital for children, Children'sHospital Boston today is the nation's leading pediatric medical center,the largest provider of health care to Massachusetts children, and theprimary pediatric teaching hospital of Harvard Medical School. Inaddition to 347 pediatric and adolescent inpatient beds andcomprehensive outpatient programs, Children's houses the world'slargest research enterprise based at a pediatric medical center, whereits discoveries benefit both children and adults. More than 500scientists, including eight members of the National Academy ofSciences, nine members of the Institute of Medicine and 10 members ofthe Howard Hughes Medical Institute comprise Children's researchcommunity. For more information about the hospital visit:

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Children's Hospital Boston. "Rare Eye-movement Disorder May Shed Light On Brain And Cardiovascular Development." ScienceDaily. ScienceDaily, 12 September 2005. <>.
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