International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B3. Sox6 is A Candidate Gene for p100H Myopathy, Heart Failure, and Sudden Neonatal Death

Nobuko Hagiwara1, Scott E. Klewer1, Ricardo A. Samson1, Drew Erickson1, Mary F. Lyon2, and Murray H. Brilliant1.
1 Department of Pediatrics, University of Arizona College of Medicine, Tucson, AZ 85724;
Mammalian Genetics unit, Medical research Council, Harwell, Didcot, Oxon OX 11 0RD, UK.

Radiation induced pink-eyed dilution (p) mutations are often associated with chromosomal deletions or rearrangements that disrupt adjacent genes of the p locus. Because of this, many of the radiation induced p mutant alleles exhibit not only diminished pigmentation but also non-pigmentation phenotypes.

p100H (pink-eyed dilution 100 Harwell) was first characterized as an early postnatal lethal mutation; mice homozygous for this mutation die within two weeks. Survival analysis revealed that one half of the mutant homozygotes die within 24 hours after birth, and during the two weeks period the surviving mutants exhibit runting, and died suddenly and often unexpectedly. We were interested in the molecular basis of this failure to thrive syndrome.

Karyotyping of the p100H mutant chromosome revealed a chromosomal inversion between 7B5 (p locus) and 7F1. Utilizing RACE (rapid amplification of cDNA ends), we identified that the inversion breakpoint in 7F1 disrupts the Sox6 gene, a member of the Sox (Sry related HMG box) transcription factor family. This family is characterized by the conserved HMG DNA binding domain. It was found that the p100H inversion separates the HMG box of the Sox6 protein from its N-terminus part, most likely generating a functionally null protein.

Detailed analysis of the p100H phenotype revealed that the homozygotes suffer from heart failure characterized by atrial-ventricular conduction defects, as well as degeneration of the skeletal muscle. Considering the sudden nature of the death, this heart failure appears to be the cause of the lethality.

We are currently investigating the expression of Sox6 during development and searching for the genes regulated by the Sox6 protein to better understand the physiological changes seen in the p100H mutant muscle tissues.

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