Rare Eye-Movement Disorders Provide Insight on How the Nervous System Develops
Genetic study of cases worldwide pinpoints intriguing mutations
January 7, 2010
Boston, Mass. - Researchers at Children's Hospital Boston have identified a key gene involved in establishing and maintaining nerve connections in the human brain and nervous system. Studying patients with a spectrum of rare inherited and acquired neurological diseases affecting voluntary movement of the eyes, face and extremities, they pinpointed eight independent mutations in this gene. They also show that the mutations have a broader neurological effect, resulting in intellectual, behavioral and social disabilities as well as progressive motor and sensory nerve degeneration. Their findings appear in the Jan. 8 issue of the journal Cell.
The eye on the right is lacking robust nerve stimulation because of a mutation in TUBB3, causing disruption of the microtubule "highway" on which kinesins travel to the nerve endings at the eye muscles. As a result, the kinesins and their vital molecular cargo (purple and yellow dots) are left stranded.
Image by Max Tischfield, Children's Hospital Boston, and Andrew Tang, Cell, adapted from Cell, Jan. 8, 2010
The spectrum of neurological diseases, now referred to as the TUBB3 syndromes, was first identified by studying patients with Congenital Fibrosis of the Extra-Ocular Muscles type 3 (CFEOM3), an inherited eye movement disorder which results in drooping eyelids and misaligned eyeballs. Some of these patients, it turned out, had CFEOM3 as part of a larger syndrome. The lab of Elizabeth Engle, MD, Professor of Neurology and Ophthalmology at Children's and senior author of the paper, has been a world leader in understanding the various forms of CFEOM, showing that they result from abnormal development of the nerves that control the muscles of the eyeball.
"Many ophthalmologists still believe CFEOM is a muscle disorder and not a nerve disorder," says Engle. In fact, she says, CFEOM3 now serves as a sensitive diagnostic marker for other neurologic disorders that interfere with the ability of the brain to wire up properly.
The newly implicated TUBB3 gene is active only in neurons and appears to be critical in the process of axon guidance--by which nerve fibers navigate to specific targets in the developing nervous system. TUBB3 manufactures a protein that is part of microtubules, hollow tubes that provide structural support to cells and also serve as highways upon which other cellular proteins known as kinesins travel. Kinesins carry vital cargo around the cell, making them essential to cell function and development.
TUBB3 is known to be unique in building microtubules that are very dynamic and can grow and shorten in response to external cues--suggesting a possible role in axon guidance.
"We wondered, why is TUBB3 only in neurons, and why is it so dynamic?" asks Max Tischfield, PhD, the paper's first author, who recently completed his graduate studies in the Engle lab. "Perhaps it has evolved a special ability to help an axon find its correct target."
Experiments in mouse and yeast models support this idea. When Tischfield mutated TUBB3 in yeast, microtubules had a diminished ability to lengthen and shorten. When mutated in mice, the animals' nerve fiber networks failed to grow toward their intended targets. Furthermore, some of the TUBB3 mutations diminished the ability of kinesins to move along microtubules, hindering their ability to transport cargo throughout nerve fibers.
These observations are consistent with studies of patients with CFEOM3 and TUBB3 mutations. Clinical examination of these patients suggests that certain nerve fibers fail to properly stimulate the eye muscles. "Dr. Engle and her colleagues have identified a new cause of an ocular disorder that affects children's eye alignment and movement, which is a rare type of strabismus. This work highlights the delicate balance of factors required for normal development of the visual system, and provides clues for better diagnosis of these conditions," says Paul A. Sieving, M.D., Ph.D., director of the National Eye Institute, part of the National Institutes of Health, which contributed funding for the study.
Further observation of patients with TUBB3 mutations revealed a broad range of neurological problems that also arise from a failure to maintain functional nerve connections: facial muscle paralysis, ambulatory difficulties, and a range of social and behavioral disturbances that can sometimes resemble certain aspects of autism. Patients with certain TUBB3 mutations also develop progressive sensory loss and muscle wasting in the feet, legs and arms due to degeneration of peripheral motor and sensory nerves.
Overall, the spectrum of neurological dysfunction shows how important microtubules and TUBB3 are to brain and nervous system, and may point the way toward future treatment strategies.
Although at present it is impossible to treat problems that originate very early in the womb, doctors may still be able to strategize treatment options for other debilitating aspects of TUBB3 syndromes, such as the progressive degeneration of peripheral motor and sensory nerves in young adults. This may be possible by administering drugs that directly affect the properties of the mutated microtubules, for example. "The more we understand the specific disorders and disease spectrum, the easier it will be to provide targeted therapy," Engle says.
The research was supported by grants from the National Eye Institute. Engle is an investigator with the Howard Hughes Medical Institute.
Citation: Max A Tischfield, PhD; Hagit N Baris, MD; Chen Wu, PhD; Guenther Rudolph, MD; Lionel Van Maldergem, MD; Wei He, BA; Wai-Man Chan, B.S.; Caroline Andrews, M.S.; Joseph Demer, MD PhD; Richard L Robertson, MD; David A Mackey, MD; Jonathan B Ruddle, MD; Thomas D Bird, MD; Irene Gottlob, MD; Christina Pieh, MD; Elias I Traboulsi, MD; Scott L Pomeroy, MD PhD; David G Hunter, MD PhD; Janet S Soul, MD; Anna Newlin, MS, CGC ; Louise J Sabol, MD; Edward J Doherty, MD; Clara E de Uzcátegui, MD; Nicholas de Uzcátegui, MD; Mary Louise Z Collins, MD; Emin C Sener, MD; Bettina Wabbels, MD; Heide Hellebrand, MD; Thomas Meitinger, MD; Teresa de Berardinis, MD; Adriano Magli, MD; Costantino Schiavi, MD; Marco Pastore-Trossello, MD; Feray Koc, MD; Agnes M Wong, MD; Alex V Levin, MD; Michael T Geraghty, MD; Maria Descartes, MD; Maree Flaherty, MD; Robyn V Jamieson, MD; Hans U Møller, MD; Ingo Meuthen, MD; David F Callen, PhD; Janet Kerwin, PhD; Susan Lindsay, PhD; Alfons Meindl, PhD; Mohan L Gupta, Jr., PhD; David Pellman, MD; Elizabeth C Engle, MD. "Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance." Cell. Jan. 8, 2009.
Children's Hospital Boston
Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is one of the nation's leading pediatric medical centers, the primary pediatric teaching hospital of Harvard Medical School, and the largest provider of health care to Massachusetts children. In addition to 396 pediatric and adolescent inpatient beds and more than 100 outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: www.childrenshospital.org/newsroom.