Genetics, Vol. 159, 715-726, October 2001, Copyright © 2001

Reciprocal Mouse and Human Limb Phenotypes Caused by Gain- and Loss-of-Function Mutations Affecting Lmbr1

Richard M. Clarka, Paul C. Markera, Erich Roesslerb, Amalia Dutrac, John C. Schimentid, Maximilian Muenkeb, and David M. Kingsleya,e
a Department of Developmental Biology, Stanford University, Stanford, California 94305-5327,
b Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1852,
c Cytogenetic and Confocal Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892,
d The Jackson Laboratory, Bar Harbor, Maine 04609
e Howard Hughes Medical Institute, Stanford University, Stanford, California 94305-5327

Corresponding author: David M. Kingsley, Howard Hughes Medical Institute, Stanford University, Beckman Ctr., B300, 279 Campus Dr., Stanford, CA 94305-5327., kingsley{at}cmgm.stanford.edu (E-mail)

Communicating editor: N. A. JENKINS

The major locus for dominant preaxial polydactyly in humans has been mapped to 7q36. In mice the dominant Hemimelic extra toes (Hx) and Hammertoe (Hm) mutations map to a homologous chromosomal region and cause similar limb defects. The Lmbr1 gene is entirely within the small critical intervals recently defined for both the mouse and human mutations and is misexpressed at the exact time that the mouse Hx phenotype becomes apparent during limb development. This result suggests that Lmbr1 may underlie preaxial polydactyly in both mice and humans. We have used deletion chromosomes to demonstrate that the dominant mouse and human limb defects arise from gain-of-function mutations and not from haploinsufficiency. Furthermore, we created a loss-of-function mutation in the mouse Lmbr1 gene that causes digit number reduction (oligodactyly) on its own and in trans to a deletion chromosome. The loss of digits that we observed in mice with reduced Lmbr1 activity is in contrast to the gain of digits observed in Hx mice and human polydactyly patients. Our results suggest that the Lmbr1 gene is required for limb formation and that reciprocal changes in levels of Lmbr1 activity can lead to either increases or decreases in the number of digits in the vertebrate limb.




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