Rm. Clark et al., Reciprocal mouse and human limb phenotypes caused by gain- and loss-of-function mutations affecting Lmbr1, GENETICS, 159(2), 2001, pp. 715-726
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 de
fects. The Lmbr1 gene is entirely within the small critical intervals recen
tly defined for both the mouse and human mutations and is misexpressed at t
he exact time that the mouse Hx phenotype becomes apparent during limb deve
lopment. This result suggests that Lmbr1 may underlie preaxial polydactyly
in both mice and humans. We have used deletion chromosomes to demonstrate t
hat the dominant mouse and human limb defects arise from gain-of-function m
utations and not from haploinsufficiency. Furthermore, we created a loss-of
-function mutation in the mouse Lmbr1 gene that causes digit number reducti
on (oligodactyly) on its own and in trans to a deletion chromosome. The los
s of digits that we observed in mice with reduced Lmbr1 activity is in cont
rast to the gain of digits observed in Hx mice and human polydactyly patien
ts. 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.