International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E50 Fine Genetic Mapping of the Bst Locus and its Modifiers

C. Z. Nash1, Q.Tang2, D. S. Rice1, J. Treadaway1, D. Goldowitz2, and J. Zuo1. 1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; 2Center for Neuroscience, The University of Tennessee, 875 Monroe Avenue, Memphis, Tennessee 38163, USA

Belly Spot and Tail (Bst) is a semi-dominant mutation that arose in the inbred strain C57BLKS (BKS). The Bst/+ mouse is characterized by a ventral white belly, a kinked tail, and normal appearing eyes with a high incidence of retinal nerve atrophy (~60%) with an embryonic onset. The retinal phenotype is variable and asymmetric and is characterized by a reduction in retinal ganglion cell numbers, misrouting axons, and a reduction of the optic nerves. The Bst/+ retinal phenotype is similar to that of the most common form of hereditary optic atrophy in humans, autosomal dominant optic atrophy (OPA1). OPA1 is also characterized by degenerate retinas and optic nerves and a wide spectrum of clinical presentation, including asymmetry. Previous studies have mapped the Bst locus to an 8.3-cM region on chromosome 16 with homologous but fractured synteny with the region on human chromosome 3 containing the OPA1 locus. In this study we generated 583 N2 backcross mice [(Bst/+/BKS X AKR)F1 X +/+/BKS], of which 197 (33.8%) were Bst/+. We refined the map of the Bst locus by selecting six MIT markers in the previously defined 8.3-cM region and genotyped the entire N2 population. We have found that the Bst locus maps to a 1-cM interval between D16Mit184 and D16Mit5. This places the Bst locus outside the region syntenic to the OPA1 locus, possibly excluding Bst as a candidate for OPA1. Only 36 (18.3%) of the 197 Bst/+ N2 mice displayed retinal deficiency, a significant reduction from the 60% of Bst/+/BKS mice with the retinal phenotype. The reduced incidence of the retinal phenotype in the Bst/+ N2 mice indicates genetic heterogeneity between the BKS and AKR strains which modifies the impact of the Bst mutation on retinal development. To scan the genome for modifiers, we selected 79 MIT markers spaced at approximately 20-cM intervals and genotyped 35 mice displaying the retinal phenotype. We typed an additional 22 markers around nominally significant loci in order to more precisely locate potential modifier loci. We have located four modifier loci demonstrating nominally significant linkage to the retinal phenotype:

Note that D15Mit22 is a suggestive modifier locus with a genome-wide p-value of 0.96 (Lander, E; Schork, N; 1994). Candidate genes located near these modifier loci and which are also involved in retinal development include Pax6, NeuroD1, Bdnf, Cat3, and Wnt7b. Identification of the Bst gene and its modifiers will greatly enhance our understanding of the development of the retina.

This work was supported in part by NIH Cancer Center Support CORE Grant CA21765, NIH/NCI Cancer Training Grant 5 R25 CA23944, and by the American Lebanese Syrian Associated Charities (ALSAC).

 


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