International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Peterson K
The Jackson Laboratory

Co-Authors: Burgess R, Johnson M, Roix J, Welsh I, O'Brien T
Institutions: The Jackson Laboratory

Chromosomal deficiencies provide a platform for uncovering developmentally important phenotypes. We have used a set of overlapping deletions surrounding the piebald locus on distal mouse chromosome 14 to perform complementation analysis to define a minimal critical region associated with respiratory distress and lethality at birth. We have cloned and characterized the candidate gene Phr1 that is located within the 480 kb respiratory distress interval. Phr1 is the ortholog of the human protein associated with myc (PAM), and the homolog of Drosophila highwire ( hiw) and C. elegans regulator of presynaptic morphology (rpm-1). The Phr1 gene contains 85 exons and encodes a 4708 aa protein that shares 96% identity with human Pam. Phr1 is dynamically expressed throughout the embryonic and postnatal nervous system. The phrenic nerve of the piebald deletion respiratory distress mutants fails to completely innervate the diaphragm and nerve terminal morphology is disrupted similar to synaptic defects seen in fly and worm mutants. These findings suggest an evolutionarily conserved role for Phr1 in synaptic development and mark it as a candidate gene for respiratory distress and ventilatory disorders in humans. We are currently performing an ENU mutagenesis screen to enhance functional annotation of the piebald deletion region. The goal of this project is the isolation of an allelic series for critical genes in the interval, such as the multi-domain target—Phr1.

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