Oculo-auriculo-vertebral spectrum (OAVS) represents a wide range of anomalies and malformations that encompass hemifacial microsomia, Goldenhar syndrome, first arch syndrome, first and second branchial arch syndrome, oculo-auriculo-vertebral dysplasia, axial mesodermal dysplasia, and the associations of CHARGE and VATER. The phenotypic spectrum of OAVS can range from simple microtia to multisystem defects that are potentially life-threatening. The frequency of OAVS in the general population is second only to oral clefts, emphasizing OAVS as a group of disorders with craniofacial manifestations with significant clinically impact. This group of heterogenous disorders have been identified in sporadic and familial cases, the later appear to be transmitted in an autosomal dominant manner. The documentation of familial occurrences of OAVS implicate yet to be identified inherited genetic factors that contribute directly to the disorder or increase an individual's susceptibility to OAVS anomalies resulting directly or indirectly in an abnormality of cell migration or tissue development. Low set ears (Lse) is an autosomal dominant branchial arch disorder in mice that shares overlapping features with some forms of OAVS. The hallmarks of Lse/+ mice are malformed and malpositioned external ears. Lse mice also have postnatal growth retardation and reduced viability. The pathogenetic mechanism of Lse is not known, nor is the identify of the Lse gene. A small panel of intraspecific backcross mice have mapped the Lse locus to the distal part of mouse chromosome 7. In order to characterize the developmental defect responsible for this autosomal dominant branchial arch disorder in mice and ultimately extend that new found knowledge to improving our understanding of OAVS in humans, the identification and characterization of the Lse gene needs to be carried out.
Specific Aim : The goal of this research proposal is to generate a high resolution linkage map of mouse chromosome 7 by defining DNA markers that closely flank the Lse locus. In future studies, the high resolution linkage map generated above will be used in conjunction with a physical map of the region to identify additional mapping markers and lead to the positional cloning of the Lse gene.
