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E. C. Bailey et al.
Hall syndrome (PHS), and postaxial polydactyly type A (PAP-A) are all
associated with variable digit defects and other developmental abnormalities. In each of these syndromes, nonsense mutations in eLI3 have
been identified that are predicted to delete specific regions of the protein. In individuals with GCPS, much of the protein is deleted, including
the zinc finger domain that is proposed to mediate DNA binding (Vortkamp et al. 1991). In PHS patients, truncations occur more distally in
the protein, preserving the zinc finger domain but removing a conserved
domain of unknown function, the post-zinc finger (PZF) domain (Kang
et al. 1997). Both PHS and GCPS are associated with craniofacial
abnormalities in addition to polydactyly. In both cases the PZF domain
is removed. PAP-A individuals have mutations in eLI3 that are predicted to truncate the protein after the PZF domain (Radhakrishna et al.
1997). These individuals have polydactyly but no craniofacial defects,
indicating that the PZF domain may be important for midline facial
patterning. The region of GLl3 distal to the PZF domain, which is lost in
all three syndromes, is believed to be necessary for normal digit formation.
Since eli3 mutations result in too many rather than too few digits, the
normal role of Gli3 may be to antagonize Shh signaling in distal limb
patterning. In support of this idea, Shh signaling during chick limb
development inhibits eli3 transcription (Marigo et al. 1996). In addition, the mouse mutation, extra toes (Xt), which is associated with a eli3
mutation similar to GCPS, results in digit overgrowth (Hui and Joyner
1993). If eli3 opposes the proliferative effects of Shh in distal limb
patterning, it is curious that eli3 mutations do not result in tumorigenesis as seen with Ptc1. Mouse models of these human diseases will help
clarify the roles of eli family members in regulating Hh signaling.
12.4.3 SHH
Hh family members are potent secreted molecules so it is not surprising
that mutations in human SHH have been implicated in disease. Mice
lacking Shh have profound patterning defects in the brain, spinal cord,
axial skeleton, and the limbs (Chiang et al. 1996). These abnormalities
closely resemble a group of birth defects in humans known as alobar
holoprosencephaly (HPE). HPE arises when the forebrain fails to divide
E. C. Bailey et al.
Hall syndrome (PHS), and postaxial polydactyly type A (PAP-A) are all
associated with variable digit defects and other developmental abnormalities. In each of these syndromes, nonsense mutations in eLI3 have
been identified that are predicted to delete specific regions of the protein. In individuals with GCPS, much of the protein is deleted, including
the zinc finger domain that is proposed to mediate DNA binding (Vortkamp et al. 1991). In PHS patients, truncations occur more distally in
the protein, preserving the zinc finger domain but removing a conserved
domain of unknown function, the post-zinc finger (PZF) domain (Kang
et al. 1997). Both PHS and GCPS are associated with craniofacial
abnormalities in addition to polydactyly. In both cases the PZF domain
is removed. PAP-A individuals have mutations in eLI3 that are predicted to truncate the protein after the PZF domain (Radhakrishna et al.
1997). These individuals have polydactyly but no craniofacial defects,
indicating that the PZF domain may be important for midline facial
patterning. The region of GLl3 distal to the PZF domain, which is lost in
all three syndromes, is believed to be necessary for normal digit formation.
Since eli3 mutations result in too many rather than too few digits, the
normal role of Gli3 may be to antagonize Shh signaling in distal limb
patterning. In support of this idea, Shh signaling during chick limb
development inhibits eli3 transcription (Marigo et al. 1996). In addition, the mouse mutation, extra toes (Xt), which is associated with a eli3
mutation similar to GCPS, results in digit overgrowth (Hui and Joyner
1993). If eli3 opposes the proliferative effects of Shh in distal limb
patterning, it is curious that eli3 mutations do not result in tumorigenesis as seen with Ptc1. Mouse models of these human diseases will help
clarify the roles of eli family members in regulating Hh signaling.
12.4.3 SHH
Hh family members are potent secreted molecules so it is not surprising
that mutations in human SHH have been implicated in disease. Mice
lacking Shh have profound patterning defects in the brain, spinal cord,
axial skeleton, and the limbs (Chiang et al. 1996). These abnormalities
closely resemble a group of birth defects in humans known as alobar
holoprosencephaly (HPE). HPE arises when the forebrain fails to divide