| Literature DB >> 22152683 |
Ilse Feenstra1, Lisenka E L M Vissers, Ronald J E Pennings, Willy Nillessen, Rolph Pfundt, Henricus P Kunst, Ronald J Admiraal, Joris A Veltman, Conny M A van Ravenswaaij-Arts, Han G Brunner, Cor W R J Cremers.
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.Entities:
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Year: 2011 PMID： 22152683 PMCID： PMC3234381 DOI： 10.1016/j.ajhg.2011.11.008
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025