Hedgehog Signaling in Animal Development and Human Disease 219
12.4 Hh Signaling in Disease and Thmorigenesis
12.4.1 PTCHI
The first indication of the importance of pte in human disease came
from the discovery of inactivating mutations in PATCHED 1 (PTCH 1) in
patients with the basal cell nevus syndrome (BCNS) (Hahn et al. 1996;
Johnson et al. 1996). BCNS, also known as Gorlin's syndrome, is an
autosomal-dominant disease associated with a wide variety of congenital defects and tumor types (Gorlin 1995). The defining characteristic in
individuals with this syndrome is the appearance of large numbers of the
skin tumor, basal cell carcinoma (BCC), during the second to third
decade of life. BCCs also arise sporadically in normal individuals and
are estimated to be the most common human cancer among individuals
of northern European descent (Miller and Weinstock 1994). In contrast
to BCNS, sporadic BCCs typically arise in low numbers and late in life.
BCNS patients often have a number of developmental defects such as
rib anomalies, spina bifida occulta, and cephalic abnormalities. A lower
frequency of patients manifest polydactyly, cleft lip and/or palate, and
occular abnormalities. It is postulated that the developmental defects of
BCNS arise by mutation of one allele of PTCHI in the germ line. The
skin tumors in BCNS individuals arise from somatic mutation of the
second PTCH 1 allele resulting in the complete loss of PTCHI function
(Gailani et al. 1996; Hahn et al. 1996; Johnson et al. 1996). The involvemept of PTCHI in BCNS demonstrates the critical function of this
protein in both prenatal and postnatal life in humans.
Inherited cancer syndromes often have a variable spectrum of phenotypic abnormalities and in certain cases, such as BRCAI mutations, this
variability correlates with the type of mutation (Gayther et al. 1995).
BCNS has considerable variability in severity and presentation. Over
80% of BCNS mutations in PTCH 1 result in protein truncations at
positions scattered throughout the protein (Gailani et al. 1996; Wicking
et al. 1997; Aszterbaum et al. 1998). An examination of 28 separate
PTCH 1 mutations revealed no apparent phenotype-genotype correlations; mutation of different PTCH 1 regions did not correlate with specific developmental defects (Wicking et al. 1997).
PTCHI mutations have been identified in a number of sporadic
tumors from otherwise normal individuals (Table 2). At least one-third
12.4 Hh Signaling in Disease and Thmorigenesis
12.4.1 PTCHI
The first indication of the importance of pte in human disease came
from the discovery of inactivating mutations in PATCHED 1 (PTCH 1) in
patients with the basal cell nevus syndrome (BCNS) (Hahn et al. 1996;
Johnson et al. 1996). BCNS, also known as Gorlin's syndrome, is an
autosomal-dominant disease associated with a wide variety of congenital defects and tumor types (Gorlin 1995). The defining characteristic in
individuals with this syndrome is the appearance of large numbers of the
skin tumor, basal cell carcinoma (BCC), during the second to third
decade of life. BCCs also arise sporadically in normal individuals and
are estimated to be the most common human cancer among individuals
of northern European descent (Miller and Weinstock 1994). In contrast
to BCNS, sporadic BCCs typically arise in low numbers and late in life.
BCNS patients often have a number of developmental defects such as
rib anomalies, spina bifida occulta, and cephalic abnormalities. A lower
frequency of patients manifest polydactyly, cleft lip and/or palate, and
occular abnormalities. It is postulated that the developmental defects of
BCNS arise by mutation of one allele of PTCHI in the germ line. The
skin tumors in BCNS individuals arise from somatic mutation of the
second PTCH 1 allele resulting in the complete loss of PTCHI function
(Gailani et al. 1996; Hahn et al. 1996; Johnson et al. 1996). The involvemept of PTCHI in BCNS demonstrates the critical function of this
protein in both prenatal and postnatal life in humans.
Inherited cancer syndromes often have a variable spectrum of phenotypic abnormalities and in certain cases, such as BRCAI mutations, this
variability correlates with the type of mutation (Gayther et al. 1995).
BCNS has considerable variability in severity and presentation. Over
80% of BCNS mutations in PTCH 1 result in protein truncations at
positions scattered throughout the protein (Gailani et al. 1996; Wicking
et al. 1997; Aszterbaum et al. 1998). An examination of 28 separate
PTCH 1 mutations revealed no apparent phenotype-genotype correlations; mutation of different PTCH 1 regions did not correlate with specific developmental defects (Wicking et al. 1997).
PTCHI mutations have been identified in a number of sporadic
tumors from otherwise normal individuals (Table 2). At least one-third