RRC ID 27745
Author Quina LA, Kuramoto T, Luquetti DV, Cox TC, Serikawa T, Turner EE.
Title Deletion of a conserved regulatory element required for Hmx1 expression in craniofacial mesenchyme in the dumbo rat: a newly identified cause of congenital ear malformation.
Journal Dis Model Mech
Abstract Hmx1 is a homeodomain transcription factor expressed in the developing eye, peripheral ganglia, and branchial arches of avian and mammalian embryos. Recent studies have identified a loss-of-function allele at the HMX1 locus as the causative mutation in the oculo-auricular syndrome (OAS) in humans, characterized by ear and eye malformations. The mouse dumbo (dmbo) mutation, with similar effects on ear and eye development, also results from a loss-of-function mutation in the Hmx1 gene. A recessive dmbo mutation causing ear malformation in rats has been mapped to the chromosomal region containing the Hmx1 gene, but the nature of the causative allele is unknown. Here we show that dumbo rats and mice exhibit similar neonatal ear and eye phenotypes. In midgestation embryos, dumbo rats show a specific loss of Hmx1 expression in neural-crest-derived craniofacial mesenchyme (CM), whereas Hmx1 is expressed normally in retinal progenitors, sensory ganglia and in CM, which is derived from mesoderm. High-throughput resequencing of 1 Mb of rat chromosome 14 from dmbo/dmbo rats, encompassing the Hmx1 locus, reveals numerous divergences from the rat genomic reference sequence, but no coding changes in Hmx1. Fine genetic mapping narrows the dmbo critical region to an interval of ∼410 kb immediately downstream of the Hmx1 transcription unit. Further sequence analysis of this region reveals a 5777-bp deletion located ∼80 kb downstream in dmbo/dmbo rats that is not apparent in 137 other rat strains. The dmbo deletion region contains a highly conserved domain of ∼500 bp, which is a candidate distal enhancer and which exhibits a similar relationship to Hmx genes in all vertebrate species for which data are available. We conclude that the rat dumbo phenotype is likely to result from loss of function of an ultraconserved enhancer specifically regulating Hmx1 expression in neural-crest-derived CM. Dysregulation of Hmx1 expression is thus a candidate mechanism for congenital ear malformation, most cases of which remain unexplained.
Volume 5(6)
Pages 812-22
Published 2012-11
DOI 10.1242/dmm.009910
PII dmm.009910
PMID 22736458
PMC PMC3484864
MeSH Animals Animals, Newborn Base Sequence Conserved Sequence / genetics* Ear / abnormalities* Ear / pathology Embryo, Mammalian / abnormalities Embryo, Mammalian / metabolism Embryo, Mammalian / pathology Eye / metabolism Eye / pathology Eye Abnormalities / genetics Eye Abnormalities / pathology Face / embryology Face / pathology Gene Expression Regulation, Developmental Genomics Homeodomain Proteins / genetics* Homeodomain Proteins / metabolism Mesoderm / metabolism* Mesoderm / pathology Mice Molecular Sequence Data Neural Crest / metabolism Neural Crest / pathology Organ Size Rats Rats, Mutant Strains Regulatory Sequences, Nucleic Acid / genetics* Sequence Deletion / genetics* Skull / embryology* Skull / metabolism Skull / pathology Transcription Factors / genetics* Transcription Factors / metabolism
IF 4.028
Times Cited 10
Rats KFRS4/Kyo(strainID=919)