Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE. Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype

Witnessing Community Violence in Residential Neighborhoods: A Mental Health Hazard for Urban Women

We examined the prevalence and psychological correlates of witnessing community violence among women of low socioeconomic status living in urban neighborhoods in the northeastern United States. Three hundred eighty-six women receiving their health care at an urban community health center were sampled to assess their violence exposures. Women were asked to report the location and timing of their exposure to witnessing violent neighborhood events in which they were not participants. The Brief Symptoms Inventory was used to assess anxiety and depressive symptoms. Controlling for marital status, educational attainment, age, and intimate partner violence victimization, women who witnessed violent acts in their neighborhoods were twice as likely to experience depressive and anxiety symptoms compared to women who did not witness community violence. Central American-born women had particularly high exposures. We conclude that witnessing neighborhood violence is a pervasive experience in this urban cohort, and is associated with anxiety and depressive symptoms, even among women who are not direct participants in violence to which they are exposed. Community violence interventions must incorporate efforts to protect the mental health of adult women who witness events in their neighborhoods

Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.Max A. Tischfield, Hagit N. Baris, Chen Wu, Guenther Rudolph, Lionel Van Maldergem, Wei He, Wai-Man Chan, Caroline Andrews, Joseph L. Demer, Richard L. Robertson, David A. Mackey, Jonathan B. Ruddle, Thomas D. Bird, Irene Gottlob, Christina Pieh, Elias I. Traboulsi, Scott L. Pomeroy, David G. Hunter, Janet S. Soul, Anna Newlin, Louise J. Sabol, Edward J. Doherty, Clara E. de Uzca´ tegui, Nicolas de Uzca´ tegui, Mary Louise Z. Collins, Emin C. Sener, Bettina Wabbels, Heide Hellebrand, Thomas Meitinger, Teresa de Berardinis, Adriano Magli, Costantino Schiavi, Marco Pastore-Trossello, Feray Koc, Agnes M. Wong, Alex V. Levin, Michael T. Geraghty, Maria Descartes, Maree Flaherty, Robyn V. Jamieson, H.U. Møller, Ingo Meuthen, David F. Callen, Janet Kerwin, Susan Lindsay, Alfons Meindl, Mohan L. Gupta, Jr., David Pellman, and Elizabeth C. Engl