Gene Map Locus: 7q36
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The organization and morphology of the developing embryo are
established through a series of inductive interactions (Marigo
et al., 1995). One family of vertebrate genes has been described
related to the Drosophila gene 'hedgehog' (hh) that encodes inductive
signals during embryogenesis (Echelard et al.,
1993; Roelink et al., 1994).
'Hedgehog' encodes a secreted protein that is involved in
establishing cell fates at several points during Drosophila
development. There are 3 known mammalian homologs of hh: Sonic
hedgehog (Shh), Indian hedgehog (Ihh; see 600726),
and desert hedgehog (Dhh) (Echelard et al.,
1993). Like its Drosophila cognate, Shh encodes a signal that is
instrumental in patterning the early embryo. It is expressed in
Hensen's node, the floorplate of the neural tube, the early gut
endoderm, the posterior of the limb buds, and throughout the
notochord. It has been implicated as the key inductive signal in
patterning of the ventral neural tube (Echelard
et al., 1993; Roelink et al., 1994),
the anterior-posterior limb axis (Riddle et
al., 1993), and the ventral somites (Johnson
et al., 1994).
The mouse, chicken, and zebrafish Shh homologs are highly
conserved (Marigo et al., 1995). Their
functional properties appear to be conserved as well. Their probable
importance in embryogenesis additionally suggests that alterations in
the human hedgehog genes might be involved in congenital anomalies.
Marigo et al. (1995) isolated human cDNA
clones of the SHH and IHH (600726)
genes. The SHH clone encodes a predicted protein 92.4% identical to
its mouse homolog, while the IHH clone encodes a protein with 94.6%
identity to its mouse homolog. IHH was expressed in adult kidney and
liver. SHH expression was not detected in adult tissues examined;
however, it was expressed in fetal intestine, liver, lung, and
kidney. By PCR analysis of DNA from a panel of rodent/human somatic
cell hybrids, Marigo et al. (1995)
assigned SHH to 7q and IHH to chromosome 2. SHH was more precisely
localized by linkage studies using a CA repeat sequence tagged site
identified in a P1 genomic clone of SHH in members of a family with
polysyndactyly, or triphalangeal thumb-polysyndactyly syndrome (TPT1;
190605),
previously reported by Tsukurov et al.
(1994). SHH was found to be closely linked to but distinct from
the TPT1 locus at 7q36; maximum lod score = 4.82 at theta = 0.05. It
was tightly linked to En2, the engrailed-2 locus (131310).
Marigo et al. (1995) mapped the mouse
homologs Shh, Ihh, and Dhh by linkage analysis of an interspecific
backcross. Shh mapped to a position 0.6 cM distal to En2 and 1.9 cM
distal to Il6, or interleukin-6 (147620),
on mouse chromosome 5. This location is closely linked to but
distinct from the murine limb mutation Hx and is in an area with
homology of synteny to human 7q36.
Porter et al. (1996) reviewed the
molecular processing of hedgehog proteins. They noted that after
signal sequence cleavage the hedgehog protein precursor of
approximately 45 kD undergoes autocatalytic internal cleavage. This
yields an approximately 20-kD N-terminal domain which has signaling
activity and a 25-kD C-terminal domain which is active in precursor
processing. Hedgehog protein autoprocessing includes peptide bond
cleavage and the attachment of a lipophilic adduct to the C-terminal
region. Porter et al. (1996) noted that
the lipophilic modification is critical for the spatially restricted
tissue localization of the hedgehog signal domain. Porter
et al. (1996) demonstrated that cholesterol is the lipophilic
moiety covalently attached to the N-terminal signaling domain during
autoprocessing and that the C-terminal domain acts as an
intramolecular cholesterol transferase. They postulated that some of
the effects of perturbed cholesterol biosynthesis on animal
development, such as those seen in Smith-Lemli-Opitz syndrome (SLO;
270400),
may be due to the fact that cholesterol is used to modify embryonic
signaling proteins.
Belloni et al. (1996) identified SHH as
a candidate gene for the autosomal dominant holoprosencephaly type 3
(HPE3; 142945)
by detailed characterization of HPE3 patient chromosome
rearrangements and contigs of the HPE3 region. Further analysis
revealed that SHH mapped approximately 250 and 15 kb centromeric of
T1 and T2, respectively (T1 and T2 represent the translocation
breakpoints in 2 unrelated patients with a mild form of HPE3).
Belloni et al. (1996) proposed that the
chromosomal rearrangements remove distal cis-acting regulatory
elements or exert long-term position effects causing aberrant
expression of the gene. Roessler et al.
(1996) defined the intron-exon boundaries of SHH by direct
sequencing and then designed primers for exon amplification and SSCP
analysis in 30 families with HPE3. The authors then identified
mutations in SHH which caused HPE3 in these families. Two families
that showed chromosome 7q36 linkage demonstrated band shifts on SSCP
of exon 1. The mutation in one family was a gly31-to-arg substitution
(600725.0001). In the second family
the mutation occurred at gln100, resulting in a stop codon (600725.0002)
and leading to synthesis of a truncated protein. In exon 2, a
nonsense mutation leading to a stop codon (600725.0003)
and 2 missense mutations (600725.0004
and 600725.0005) were identified.
Roessler et al. (1996) noted that loss of
one SHH allele was sufficient to cause HPE in humans, whereas both
Shh alleles need to be lost to produce a similar phenotype in mice
(Chiang et al., 1996).
Ericson et al. (1996) analyzed the role
of SHH signaling in the specification of vertebrate motor neuron
identity using cultured explants of chick neural plate, neural tube
and notochord tissue, and antibodies which block SHH signaling. They
noted that the identity and pattern of cell types generated in the
ventral neural tube is controlled by the notochord, an axial
mesodermal organizing center. Previous studies revealed that the
notochord secretes a locally acting factor that induces
differentiation of the floor plate cells at the ventral midline of
the neural tube and a diffusible factor that can initiate motor
neuron differentiation (Placzek, 1995).
Ericson et al. (1996) demonstrated that SHH
function is required for the short-range induction of floor plate
cells by the notochord. They also showed that SHH function is
required independently for the induction of motor neurons by both the
notochord and midline neural cells. Ericson et
al. (1996) showed that motor neuron generation depends on 2
critical periods of SHH signaling: an early period, during which the
neural plate cells are converted to ventralized progenitors, and a
late period, during which SHH drives the differentiation of
ventralized progenitors into motor neurons. They reported further
that the ambient SHH concentration during the late period determines
whether ventralized progenitors differentiate into motor neurons or
interneurons, thus defining the pattern of neuronal cell types
generated in the neural tube.
Marigo et al. (1996) reported that the
Patched (Ptc) gene product (601309)
is the receptor for sonic hedgehog. This was demonstrated by carrying
out Shh binding studies on Xenopus laevis oocytes which had been
injected with Ptc mRNA. Binding was shown to be dependent on
glycosylation of Ptc and on the 2 large extracellular domains of Ptc.
Independently and simultaneously, Stone et al
(1996) reported that epitope-tagged N-terminal Shh peptide binds
specifically to mouse Ptc. They also demonstrated that Ptc and Smo
(601500)
form a complex, and that Shh binds the complex. Stone
et al. (1996) noted that genetic mutations leading to a truncated
or unstable Ptc protein are associated with familial or sporadic
basal cell carcinoma (BCC). They suggested that this finding,
combined with the fact that Ptc is a high-affinity binding protein
for Shh, suggests that the Hedgehog system may provide mitogenic or
differentiative signals to basal cells in the skin throughout life.
Stone et al. (1996) raised the possibility
that basal cell nevus syndrome (BCNS; 109400)
and BCC might result from constitutive activation of Smo, which
becomes oncogenic after its release from inhibition by Ptc.
On the basis of their studies in Drosophila, Chen
and Struhl (1996) presented evidence that Ptc acts as a receptor
for hedgehog (Hh) proteins. They suggested a novel signal
transduction mechanism in which Hh proteins bind to Ptc or to a
Ptc-Smo complex and thereby induce Smo activity. Their results showed
further that Ptc limits the range of Hh action and that the high
levels of Ptc induced by Hh serve to sequester any free Hh and
thereby create a barrier to its further movement.
For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
Chiang et al. (1996) generated mice
that were homozygous for a disrupted Sonic hedgehog gene by using
homologous recombination in embryonic stem cells. Morphological
studies in these mice revealed defects in the establishment of
maintenance of mid-line structures such as the notochord and
floorplate. Other defects observed included absence of distal limb
structures, cyclopia, absence of ventral cell types within the
neural tube, and absence of the spinal column and most of the
ribs. Chiang et al. (1996) reported that
defects in all tissues extend beyond the normal sites of Shh
transcription, and that this observation confirmed the proposed
role of Shh protein as an extracellular signal required for the
tissue organizing properties of several vertebrate patterning
centers.
Oro et al. (1997) showed that
transgenic mice overexpressing SHH in the skin developed many
features of the basal cell nevus syndrome, demonstrating that SHH
is sufficient to induce basal cell carcinomas (BCCs) in mice. The
data suggested that SHH may have a role in human tumorigenesis.
Activating mutations of SHH or another 'hedgehog' gene may be an
alternative pathway for BCC formation in humans. The human
mutation his133tyr (his134tyr in mouse) is a candidate. It is
distinct from loss-of-function mutations reported for individuals
with holoprosencephaly. His133 lies adjacent in the catalytic site
to his134 (mouse his135), one of the conserved residues thought to
be necessary for catalysis. Oro et al.
(1997) suggested that SHH may be a dominant oncogene in
multiple human tumors, a mirror of the tumor suppressor activity
of the opposing 'patched' (PTCH; 601309)
gene. The rapid and frequent appearance of Shh-induced tumors in
the mice suggested that disruption of the SHH-PTC pathway is
sufficient to create BCCs. The mouse BCCs appeared within the
first 4 days of skin development, unlike mouse squamous neoplasia
where tumors arise 1 to 12 months after oncogene expression. The
kinetics of the tumors in these mice were consistent with previous
clinical and epidemiologic data, which suggested that BCCs, in
contrast to melanomas and squamous carcinomas, lack precursor or
intermediate cellular phenotypes. The gene PTCH joins APC
(175100)
in a class of genes instrumental for controlling early epithelial
proliferation. Mutations in APC cause familial adenomatous
polyposis, a condition that predisposes individuals to many benign
polyps, akin to the hundreds of nodular BCCs that can occur in
patients with the basal cell nevus syndrome (BCNS; 109400).
Nodular BCCs are reminiscent of polyps in colonic epithelium, as
both lack aneuploidy and are locally invasive.
Litingtung et al. (1998) found that
mice with a targeted deletion of Shh have foregut defects that are
apparent as early as embryonic day 9.5, when the tracheal
diverticulum begins to outgrow. Homozygous Shh-null mutant mice
showed esophageal atresia/stenosis, tracheoosophageal fistula, and
tracheal and lung anomalies, features similar to those observed in
humans with foregut defects. The lung mesenchyme showed enhanced
cell death, decreased cell proliferation, and downregulation of
Shh target genes. These results indicated that Shh is required for
the growth and differentiation of the esophagus, trachea, and
lung, and suggested that mutations in SHH and its signaling
components may be involved in foregut defects in humans. Of
relevance is the demonstration of Motoyama
et al. (1998) that Gli2 (165230)
and Gli3 (165240),
which are involved in the transduction of Shh signal, are
essential to the formation of lung, trachea, and esophagus.
Roessler et al. (1996) identified a GGG-to-AGG transition resulting in a gly31-to-arg substitution of the SHH gene in a family with HPE3 (142945). This exon 1 residue is conserved in hedgehog proteins and is adjacent to the putative signal cleavage site.
Roessler et al. (1996) identified a CAG-to-TAG transition resulting in a gln100-to-ter nonsense mutation of the SHH gene in a family with HPE3.
Roessler et al. (1996) identified a AAG-to-TAG transversion resulting in a lys105-to-ter nonsense mutation of the SHH gene in a large multigenerational family with HPE3.
Roessler et al. (1996) identified a TGG-to-GGG transversion resulting in a trp117-to-gly substitution of the SHH gene in a family with HPE3. The trp117 residue is invariant in all hedgehog protein sequences and occurs immediately following the first alpha-helix of the murine Shh N fragment.
Roessler et al. (1996) identified a
TGG-to-CGG transversion resulting in a trp117-to-arg substitution
in the SHH gene in a family with HPE3. The trp117 residue is
invariant in all of the hedgehog protein sequences and occurs
immediately following the first alpha-helix of the murine Shh N
fragment.
Victor A. McKusick - updated : 8/28/1998
Ada Hamosh - updated : 4/9/1998
Victor A. McKusick - updated : 5/1/1997
Moyra Smith - updated : 1/7/1997
Moyra Smith - updated : 11/19/1996
Moyra Smith - updated : 11/13/1996
Moyra Smith - updated : 11/4/1996
Moyra Smith - updated : 10/11/1996
Moyra Smith - updated : 10/2/1996
Moyra Smith - updated : 5/18/1996
Victor A. McKusick : 8/17/1995
terry : 8/16/1999
alopez : 8/31/1998
terry : 8/28/1998
carol : 7/27/1998
alopez : 4/9/1998
mark : 7/31/1997
mark : 7/31/1997
mark : 7/30/1997
jamie : 5/29/1997
joanna : 5/29/1997
mark : 5/1/1997
terry : 5/1/1997
mark : 1/10/1997
jamie : 1/8/1997
jamie : 1/7/1997
mark : 1/7/1997
mark : 11/19/1996
mark : 11/13/1996
mark : 11/13/1996
mark : 11/13/1996
mark : 11/4/1996
mark : 11/4/1996
mark : 10/15/1996
mark : 10/11/1996
terry : 10/3/1996
mark : 10/2/1996
carol : 5/21/1996
mark : 5/21/1996
mark : 5/21/1996
carol : 5/18/1996
terry : 9/11/1995
mark : 8/17/1995