Tan X.,U.S. National Cancer Institute |
Anzick S.L.,U.S. National Cancer Institute |
Khan S.G.,U.S. National Cancer Institute |
Ueda T.,U.S. National Cancer Institute |
And 11 more authors.
Human Mutation | Year: 2013
Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma. © 2013 WILEY PERIODICALS, INC.
Grimsley-Myers C.M.,University of Virginia |
Sipe C.W.,University of Virginia |
Wu D.K.,National Institute of Deafness and Communication Disorders |
Lu X.,University of Virginia
Developmental Biology | Year: 2012
Development of the mammalian inner ear requires coordination of cell proliferation, cell fate determination and morphogenetic movements. While significant progress has been made in identifying developmental signals required for inner ear formation, less is known about how distinct signals are coordinated by their downstream mediators. Members of the Rac family of small GTPases are known regulators of cytoskeletal remodeling and numerous other cellular processes. However, the function of Rac GTPases in otic development is largely unexplored. Here, we show that Rac1 and Rac3 redundantly regulate many aspects of inner ear morphogenesis. While no morphological defects were observed in Rac3 -/- mice, Rac1 CKO; Rac3 -/- double mutants displayed enhanced vestibular and cochlear malformations compared to Rac1 CKO single mutants. Moreover, in Rac1 CKO; Rac3 -/- mutants, we observed compromised E-cadherin-mediated cell adhesion, reduced cell proliferation and increased cell death in the early developing otocyst, leading to a decreased size and malformation of the membranous labyrinth. Finally, cochlear extension was severely disrupted in Rac1 CKO; Rac3 -/- mutants, accompanied by a loss of epithelial cohesion and formation of ectopic sensory patches underneath the cochlear duct. The compartmentalized expression of otic patterning genes within the Rac1 CKO; Rac3 -/- mutant otocyst was largely normal, however, indicating that Rac proteins regulate inner ear morphogenesis without affecting cell fate specification. Taken together, our results reveal an essential role for Rac GTPases in coordinating cell adhesion, cell proliferation, cell death and cell movements during otic development. © 2011 Elsevier Inc.
Faroqi-Shah Y.,University of Maryland University College |
Kling T.,Johns Hopkins University |
Solomon J.,Medical Numerics |
Liu S.,National Institute of Deafness and Communication Disorders |
And 2 more authors.
GPS Solutions | Year: 2014
Background: Three aspects of language production are impaired to different degrees in individuals with post-stroke aphasia: ability to repeat words and nonwords, name pictures, and produce sentences. These impairments often persist into the chronic stages, and the neuroanatomical distribution of lesions associated with chronicity of each of these impairments is incompletely understood.Aims: The primary objective of this study was to investigate the lesion correlates of picture naming, sentence production, and nonword repetition deficits in the same participant group because most prior lesion studies have mapped single language impairments. The broader goal of this study was to investigate the extent and degree of overlap and uniqueness among lesions resulting in these deficits in order to advance the current understanding of functional subdivision of neuroanatomical regions involved in language production.Methods & Procedures: In this study, lesion-symptom mapping was used to determine if specific cortical regions are associated with nonword repetition, picture naming, and sentence production scores. Structural brain images and behavioural performance of 31 individuals with post-stroke left hemisphere lesions and a diagnosis of aphasia were used in the lesion analysis.Outcomes & Results: Each impairment was associated with mostly unique, but a few shared lesions. Overall, sentence and repetition deficits were associated with left anterior perisylvian lesions, including the pars opercularis and triangularis of the inferior frontal lobe, anterior superior temporal gyrus, anterior portions of the supramarginal gyrus, the putamen, and anterior portions of the insula. In contrast, impaired picture naming was associated with posterior perisylvian lesions including major portions of the inferior parietal lobe and middle temporal gyrus. The distribution of lesions in the insula was consistent with this antero-posterior perisylvian gradient. Significant voxels in the posterior planum temporale were associated with a combination of all three deficits.Conclusions: These findings emphasise the participation of each perisylvian region in multiple linguistic functions, suggesting a many(functions)-to-many(networks) framework while also identifying functional subdivisions within each region.