Human Molecular Genetics Advance Access originally published online on December 15, 2005
Human Molecular Genetics 2006 15(2):319-327; doi:10.1093/hmg/ddi449
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Xcat, a novel mouse model for Nance–Horan syndrome inhibits expression of the cytoplasmic-targeted Nhs1 isoform
1F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 2Department of Biological Sciences, University of Delaware, Newark, DE, USA, 3NHGRI, NIH, Bethesda, MD, USA and 4Institute of Human Genetics, GSF-National Research Center for Environment and Health, Neuherberg, Germany
* To whom correspondence should be addressed at: University of Pennsylvania School of Medicine, Stellar-Chance Building Room 313, 422 Curie Boulevard, Philadelphia, PA 19104, USA. Tel: +1 2158980305; Fax: +1 2155736728; Email: stamboli{at}mail.med.upenn.edu
Received October 4, 2005; Accepted December 4, 2005
Nance–Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features and mental retardation. A recent report suggests that the novel gene NHS1 is involved in this disorder due to the presence of point mutations in NHS patients. A possible mouse model for NHS, Xcat, was mapped to a 2.11 Mb interval on the X-chromosome. Sequence and FISH analysis of the X-chromosome region containing the Xcat mutation reveal a large insertion between exons 1 and 2 of the mouse Nhs1 gene. The insertion inhibits the expression of the Nhs1 isoform containing exon 1 and results in exclusive expression of the alternative isoform containing exon 1A. Quantitative RT–PCR of Xcat cDNA shows reduced levels of Nhs1 transcripts. The Nhs1 protein is strongly expressed within the cytoplasm of elongating lens fiber cells from wild-type neonate lens, but is significantly reduced within the Xcat lens. Transient transfection studies of CHO cells with Nhs1–GFP fusion proteins were done to determine whether the amino acids encoded by exon 1 were critical for protein localization. We found the presence of Nhs1 exon 1 critical for localization of the fusion protein to the cytoplasm, whereas fusion proteins lacking Nhs1 exon 1 are predominantly nuclear. These results indicate that the first exon of Nhs1 contains crucial information required for the proper expression and localization of Nhs1 protein. Inhibition of expression of the exon 1 containing isoform results in the abnormal phenotype of Xcat.
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