Unique Alterations of an Ultraconserved Non-Coding Element in the 3′UTR of ZIC2 in Holoprosencephaly

Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp ele...

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Published inPloS one Vol. 7; no. 7; p. e39026
Main Authors Roessler, Erich, Hu, Ping, Hong, Sung-Kook, Srivastava, Kshitij, Carrington, Blake, Sood, Raman, Petrykowska, Hanna, Elnitski, Laura, Ribeiro, Lucilene A., Richieri-Costa, Antonio, Feldman, Benjamin, Odenwald, Ward F., Muenke, Maximilian
Format Journal Article
LanguageEnglish
Published San Francisco Public Library of Science 31.07.2012
Subjects
3' Untranslated regions
Alterations
Biology
Evolution
Genes
Genetic diversity
Genetics
Genomes
Holoprosencephaly
Identification
Laboratories
Medicine
Molecular biology
Mutation
Regulatory sequences
Risk assessment
Transcription factors
Vertebrates
Zebrafish
United States > US
Maryland
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Summary:Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3′ untranslated region (3′UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases.
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Conceived and designed the experiments: ER S-KH BF WFO MM. Performed the experiments: ER PH S-KH KS BC RS HP. Analyzed the data: ER LE BF WFO. Contributed reagents/materials/analysis tools: ER LAR AR-C. Wrote the paper: ER MM.
Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0039026