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Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans
Authors:Feenstra Ilse  Vissers Lisenka E L M  Pennings Ronald J E  Nillessen Willy  Pfundt Rolph  Kunst Henricus P  Admiraal Ronald J  Veltman Joris A  van Ravenswaaij-Arts Conny M A  Brunner Han G  Cremers Cor W R J
Affiliation:1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands;2Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disease, Nijmegen 6500 HB, The Netherlands;3Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands;4Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen, Nijmegen 6500 HB, The Netherlands;5Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen 9700 RB, The Netherlands
Abstract:Congenital aural atresia (CAA) can occur as an isolated congenital malformation or in the context of a number of monogenic and chromosomal syndromes. CAA is frequently seen in individuals with an 18q deletion, which is characterized by intellectual disability, reduced white-matter myelination, foot deformities, and distinctive facial features. Previous work has indicated that a critical region for CAA is located in 18q22.3. We studied four individuals (from two families) with CAA and other features suggestive of an 18q deletion, and we detected overlapping microdeletions in 18q22.3 in both families. The minimal region of deletion overlap (72.9-73.4 Mb) contained only one known gene, TSHZ1, which was recently shown to be important for murine middle-ear development. Sequence analysis of the coding exons in TSHZ1 in a cohort of 11 individuals with isolated, nonsyndromic bilateral CAA revealed two mutations, c.723G>A (p.Trp241X) and c.946_947delinsA (p.Pro316ThrfsX16), and both mutations predicted a loss of function. Together, these results demonstrate that hemizygosity of TSHZ1 leads to congenital aural atresia as a result of haploinsufficiency.
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