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Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1
R M Clark1, P C Marker, E Roessler
1Department of Developmental Biology, Stanford University, Stanford, California 94305-5327, USA.
Genetics
|October 19, 2001
Summary
The Lmbr1 gene is implicated in limb development. Gain-of-function mutations cause polydactyly (extra digits), while loss-of-function mutations cause oligodactyly (fewer digits), revealing Lmbr1
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- Dominant preaxial polydactyly in humans is linked to chromosome 7q36.
- Homologous mouse mutations (Hemimelic extra toes and Hammertoe) cause similar limb defects.
Purpose of the Study:
- Investigate the role of the Lmbr1 gene in limb development.
- Determine if Lmbr1 mutations cause polydactyly in mice and humans.
Main Methods:
- Mapped human and mouse limb defect loci to homologous chromosomal regions.
- Analyzed Lmbr1 gene expression during mouse limb development.
- Utilized deletion chromosomes to distinguish gain-of-function from haploinsufficiency.
- Created a loss-of-function Lmbr1 mutation in mice.
Main Results:
- The Lmbr1 gene is located within the critical interval for mouse and human limb mutations.
- Misexpression of Lmbr1 correlates with the onset of the mouse Hemimelic extra toes phenotype.
- Limb defects result from gain-of-function mutations, not haploinsufficiency.
- Loss-of-function Lmbr1 mutations cause digit reduction (oligodactyly).
Conclusions:
- The Lmbr1 gene is essential for vertebrate limb formation.
- Altered Lmbr1 activity levels can result in either polydactyly or oligodactyly.