Genetics, Vol. 155, 291-300, May 2000, Copyright © 2000

Genomic, Transcriptional and Mutational Analysis of the Mouse microphthalmia Locus

Jón H. Hallssona, Jack Favorb, Colin Hodgkinsonc, Tom Glaserc, M. Lynn Lamoreuxd, Rannveig Magnúsdóttira, Gunnar J. Gunnarssona, Hope O. Sweete, Neal G. Copelandf, Nancy A. Jenkinsf, and Eiríkur Steingrímssona
a Department of Biochemistry and Molecular Biology, School of Medicine, University of Iceland, 101 Reykjavík, Iceland,
b GSF-Institute of Mammalian Genetics, D-85764 Neuherberg, Germany,
c Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109,
d Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843,
e The Jackson Laboratory, Bar Harbor, Maine 04609
f Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Corresponding author: Eiríkur Steingrímsson, Department of Biochemistry and Molecular Biology, School of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavík, Iceland., eirikurs{at}hi.is (E-mail)

Communicating editor: C. KOZAK

Mouse microphthalmia transcription factor (Mitf) mutations affect the development of four cell types: melanocytes, mast cells, osteoclasts, and pigmented epithelial cells of the eye. The mutations are phenotypically diverse and can be arranged in an allelic series. In humans, MITF mutations cause Waardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant disorders resulting in deafness and hypopigmentation. Mitf mice thus represent an important model system for the study of human disease. Here we report the complete exon/intron structure of the mouse Mitf gene and show it to be similar to the human gene. We also found that the mouse gene is transcriptionally complex and is capable of generating at least 13 different Mitf isoforms. Some of these isoforms are missing important functional domains of the protein, suggesting that they might play an inhibitory role in Mitf function and signal transduction. In addition, we determined the molecular basis for six microphthalmia mutations. Two of the mutations are reported for the first time here (Mitfmi-enu198 and Mitfmi-x39), while the others (Mitfmi-ws, Mitfmi-bws, Mitfmi-ew, and Mitfmi-di) have been described but the molecular basis for the mutation not determined. When analyzed in terms of the genomic and transcriptional data presented here, it is apparent that these mutations result from RNA processing or transcriptional defects. Interestingly, three of the mutations (Mitfmi-x39, Mitfmi-bws, and Mitfmi-ws) produce proteins that are missing important functional domains of the protein identified in in vitro studies, further confirming a biological role for these domains in the whole animal.





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