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Human Molecular Genetics Advance Access published online on November 3, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi005
© 2004 by Oxford University Press
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Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia

Yien-Ming Kuo 1, Jacque L. Duncan 2, Shawn K. Westaway 3, Haidong Yang 2, George Nune 2, Eugene Yujun Xu 4, Susan J. Hayflick 3, and Jane Gitschier Ph.D.5*

1 Departments of Medicine, University of California, San Francisco and Howard Hughes Medical Institute, CA, USA
2 Ophthalmology, University of California, San Francisco and Howard Hughes Medical Institute, CA, USA
3 Pediatrics, University of California, San Francisco and Howard Hughes Medical Institute, CA, USA
4 Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco and Howard Hughes Medical Institute, CA, USA
5 Departments of Medicine, HSE-901, Box 0794, University of California, San Francisco and Howard Hughes Medical Institute, CA, 94143, USA

* To whom correspondence should be addressed.
Jane Gitschier, E-mail: gitschi{at}itsa.ucsf.edu


  Abstract

Pantothenate-kinase associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment, and reduced pupillary constriction response compared to those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongating and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight compared to their wild-type littermates, however dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and spermatozoa.


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