Human Molecular Genetics Advance Access originally published online on November 3, 2004
Human Molecular Genetics 2005 14(1):49-57; doi:10.1093/hmg/ddi005
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved
Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia
1Department of Medicine, 2Department of Pediatrics, 3Department of Ophthalmology, 4Department of Obstetrics, Gynecology and Reproductive Sciences and 5Howard Hughes Medical Institute, University of California, San Francisco, CA, USA and 6Department of Molecular and Medical Genetics, Oregon Health and Science University, OR, USA
* To whom correspondence should be addressed at: HSE-901, PO Box 0794, University of California, San Francisco, CA 94143, USA. Tel: +1 4154768729; Fax: +1 4155020720; Email: gitschi{at}itsa.ucsf.edu
Received July 30, 2004; Accepted October 22, 2004
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 when compared with 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 elongated 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 when compared with 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 the spermatozoa.
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