Adult polycystic kidney disease (APKD) is typically a late onset,
autosomal dominant disorder characterised by multiple renal
cysts. It is one of the most common genetic diseases in humans
and the incidence may be as high as 1 in 1000. There is
considerable variation in the age at which end stage renal
failure is reached and the frequency of hypertension, urinary
tract infections, and hepatic cysts. Approximately 20% of APKD
patients have end stage renal failure by the age of 50 and 70%
by the age of 70, with 5% of all end stage renal failure being due
to APKD. A high incidence of colonic diverticulae associated
with a risk of colonic perforation is reported in APKD patients
with end stage renal failure. An increased prevalence of 4–5%
for intracranial aneurysms has been suggested, compared to the
prevalence of 1% in the general population. There may also be
an increased prevalence of mitral, aortic and tricuspid
regurgitation, and tricuspid valve prolapse in APKD.
Saturday, April 11, 2009
affected individuals have renal cysts d
All affected individuals have renal cysts detectable on
ultrasound scan by the age of 30. Screening young adults at risk
will identify those asymptomatic individuals who are affected
and require annual screening for hypertension, urinary tract
infections and decreased renal function. Children diagnosed
under the age of one year may have deterioration of renal
function during childhood, but there is little evidence that
early detection in asymptomatic children affects prognosis.
ultrasound scan by the age of 30. Screening young adults at risk
will identify those asymptomatic individuals who are affected
and require annual screening for hypertension, urinary tract
infections and decreased renal function. Children diagnosed
under the age of one year may have deterioration of renal
function during childhood, but there is little evidence that
early detection in asymptomatic children affects prognosis.
locus heterogeneity in APKD
There is locus heterogeneity in APKD with at least three loci
identified by linkage studies and two genes cloned. The gene
for APKD1 on chromosome 16p encodes a protein called
polycystin-1, which is an integral membrane protein involved in
cell–cell/matrix interactions. The protein encoded by the gene
for APKD2 on chromosome 4 has been called polycystin-2.
Mutation analysis is not routinely undertaken, but linkage
studies may be used in conjunction with ultrasound scanning to
detect asymptomatic gene carriers.
identified by linkage studies and two genes cloned. The gene
for APKD1 on chromosome 16p encodes a protein called
polycystin-1, which is an integral membrane protein involved in
cell–cell/matrix interactions. The protein encoded by the gene
for APKD2 on chromosome 4 has been called polycystin-2.
Mutation analysis is not routinely undertaken, but linkage
studies may be used in conjunction with ultrasound scanning to
detect asymptomatic gene carriers.
Severe congenital deafness
Severe congenital deafness affects approximately 1 in 1000
infants. This may occur as an isolated deafness as or part of a
syndrome. At least half the cases of congenital deafness have a
genetic aetiology. Of genetic cases, approximately 66% are
autosomal recessive, 31% are autosomal dominant, 3% are
X linked recessive. Over 30 autosomal recessive loci have been
identified. This means that two parents with autosomal
recessive congenital deafness will have no deaf children
infants. This may occur as an isolated deafness as or part of a
syndrome. At least half the cases of congenital deafness have a
genetic aetiology. Of genetic cases, approximately 66% are
autosomal recessive, 31% are autosomal dominant, 3% are
X linked recessive. Over 30 autosomal recessive loci have been
identified. This means that two parents with autosomal
recessive congenital deafness will have no deaf children
Connexin 26 mutations
Mutations in the connexin 26 gene (CX26) on chromosome 13
have been found in severe autosomal recessive congenital
deafness and may account for up to 50% of cases. One specific
mutation, 30delG accounts for over half of the mutations
detected. The carrier frequency for CX26 mutations in the
general population is around 1 in 35. Mutation analysis in
affected children enables carrier detection in relatives, early
diagnosis in subsequent siblings and prenatal diagnosis if
requested.
have been found in severe autosomal recessive congenital
deafness and may account for up to 50% of cases. One specific
mutation, 30delG accounts for over half of the mutations
detected. The carrier frequency for CX26 mutations in the
general population is around 1 in 35. Mutation analysis in
affected children enables carrier detection in relatives, early
diagnosis in subsequent siblings and prenatal diagnosis if
requested.
The CX26 gene
The CX26 gene encodes a gap junction protein that forms
plasma membrane channels that allow small molecules and
ions to move from one cell to another. These channels play a
role in potassium homeostasis in the cochlea which is
important for inner ear function.
plasma membrane channels that allow small molecules and
ions to move from one cell to another. These channels play a
role in potassium homeostasis in the cochlea which is
important for inner ear function.
Pendred syndrome
Pendred syndrome is an autosomal recessive form of deafness
due to cochlear abnormality that is associated with a thyroid
goitre. It may account for up to 10% of hereditary deafness.
Not all patients have thyroid involvement at the time the
deafness is diagnosed and the perchlorate discharge test has
been used in diagnosis.
The gene for Pendred syndrome, called PDS, was isolated in
1997 and is located on chromosome 7. The protein product
called pendrin, is closely related to a number of sulphate
transporters and is expressed in the thyroid gland. Mutation
detection enables diagnosis and carrier testing within affected
families.
due to cochlear abnormality that is associated with a thyroid
goitre. It may account for up to 10% of hereditary deafness.
Not all patients have thyroid involvement at the time the
deafness is diagnosed and the perchlorate discharge test has
been used in diagnosis.
The gene for Pendred syndrome, called PDS, was isolated in
1997 and is located on chromosome 7. The protein product
called pendrin, is closely related to a number of sulphate
transporters and is expressed in the thyroid gland. Mutation
detection enables diagnosis and carrier testing within affected
families.
Eye disorders
Both childhood onset severe visual handicap and later onset
progressive blindness commonly have a genetic aetiology.
X linked inheritance is common, but there are also many
autosomal dominant and recessive conditions. Leber hereditary
optic neuropathy is a late onset disorder causing rapid
development of blindness that follows maternal inheritance
from an underlying mitochondrial DNA mutation. Genes for a
considerable number of a mendelian eye disorders have been
identified. Mutation analysis will increasingly contribute to
clinical diagnosis since the mode of inheritance can often not
be determined from clinical presentation in sporadic cases.
Mutation analysis will also be particularly useful for carrier
detection in females with a family history of X linked
blindness.
progressive blindness commonly have a genetic aetiology.
X linked inheritance is common, but there are also many
autosomal dominant and recessive conditions. Leber hereditary
optic neuropathy is a late onset disorder causing rapid
development of blindness that follows maternal inheritance
from an underlying mitochondrial DNA mutation. Genes for a
considerable number of a mendelian eye disorders have been
identified. Mutation analysis will increasingly contribute to
clinical diagnosis since the mode of inheritance can often not
be determined from clinical presentation in sporadic cases.
Mutation analysis will also be particularly useful for carrier
detection in females with a family history of X linked
blindness.
Retinitis pigmentosa
Retinitis pigmentosa (RP) is the most common type of inherited
retinal degenerative disorder. Like many other eye conditions it
is genetically heterogeneous, with autosomal dominant (25%),
autosomal recessive (50%), and X linked (25%) cases. In
isolated cases the mode of inheritance cannot be determined
from clinical findings, except that X linked inheritance can be
identified if female relatives have pigmentary abnormalities and
an abnormal electroretinogram. Linkage studies have identified
three gene loci for X linked retinitis pigmentosa and mutations
in the rhodopsin and peripherin genes occur in a significant
proportion of dominant cases.
retinal degenerative disorder. Like many other eye conditions it
is genetically heterogeneous, with autosomal dominant (25%),
autosomal recessive (50%), and X linked (25%) cases. In
isolated cases the mode of inheritance cannot be determined
from clinical findings, except that X linked inheritance can be
identified if female relatives have pigmentary abnormalities and
an abnormal electroretinogram. Linkage studies have identified
three gene loci for X linked retinitis pigmentosa and mutations
in the rhodopsin and peripherin genes occur in a significant
proportion of dominant cases.
Epidermolysis bullosa
Epidermolysis bullosa (EB) is a clinically and genetically
heterogeneous group of blistering skin diseases. The main types
are designated as simplex, junctional and dystrophic, based on
ultrastructural analysis of skin biopsies. EB simplex causes
recurrent, non-scarring blisters from increased skin fragility.
The majority of cases are due to autosomal dominant mutations
in either the keratin 5 or keratin 14 genes. A rare autosomal
recessive syndrome of EB simplex and muscular dystrophy is
due to a mutation in a gene encoding plectin. Junctional EB is
characterised by extreme fragility of the skin and mucus
membranes with blisters occurring after minor trauma or
friction. Both lethal and non-lethal autosomal recessive forms
occur and mutations have been found in several genes that
encode basal lamina proteins, including laminin 5,
integrin and type XVII collagen. In dystrophic EB the
blisters cause mutilating scars and gastrointestinal strictures,
and there is an increased risk of severe squamous cell
carcinomas in affected individuals. Autosomal recessive and
dominant cases caused by mutations in the collagen
VII gene.
heterogeneous group of blistering skin diseases. The main types
are designated as simplex, junctional and dystrophic, based on
ultrastructural analysis of skin biopsies. EB simplex causes
recurrent, non-scarring blisters from increased skin fragility.
The majority of cases are due to autosomal dominant mutations
in either the keratin 5 or keratin 14 genes. A rare autosomal
recessive syndrome of EB simplex and muscular dystrophy is
due to a mutation in a gene encoding plectin. Junctional EB is
characterised by extreme fragility of the skin and mucus
membranes with blisters occurring after minor trauma or
friction. Both lethal and non-lethal autosomal recessive forms
occur and mutations have been found in several genes that
encode basal lamina proteins, including laminin 5,
integrin and type XVII collagen. In dystrophic EB the
blisters cause mutilating scars and gastrointestinal strictures,
and there is an increased risk of severe squamous cell
carcinomas in affected individuals. Autosomal recessive and
dominant cases caused by mutations in the collagen
VII gene.
Mutation analysis
Mutation analysis in specialist centres enables prenatal
diagnosis in families, which is particularly appropriate for the
more severe forms of the disease. Skin disorders such as
epidermolysis bullosa provide potential candidates for gene
therapy, since the affected tissue is easily accessible and
amenable to a variety of potential in vivo and ex vivo gene
therapy approaches.
diagnosis in families, which is particularly appropriate for the
more severe forms of the disease. Skin disorders such as
epidermolysis bullosa provide potential candidates for gene
therapy, since the affected tissue is easily accessible and
amenable to a variety of potential in vivo and ex vivo gene
therapy approaches.
Genetics of cancer
Cellular proliferation is under genetic control and
development of cancer is related to a combination of
environmental mutagens, somatic mutation and inherited
predisposition. Molecular studies have shown that several
mutational events, that enhance cell proliferation and increase
genome instability, are required for the development of
malignancy. In familial cancers one of these mutations is
inherited and represents a constitutional change in all cells,
increasing the likelihood of further somatic mutations
occurring in the cells that lead to tumour formation.
Chromosomal translocations have been recognised for many
years as being markers for, or the cause of, certain neoplasms,
and various oncogenes have been implicated.
development of cancer is related to a combination of
environmental mutagens, somatic mutation and inherited
predisposition. Molecular studies have shown that several
mutational events, that enhance cell proliferation and increase
genome instability, are required for the development of
malignancy. In familial cancers one of these mutations is
inherited and represents a constitutional change in all cells,
increasing the likelihood of further somatic mutations
occurring in the cells that lead to tumour formation.
Chromosomal translocations have been recognised for many
years as being markers for, or the cause of, certain neoplasms,
and various oncogenes have been implicated.
The risk that a common cancer
The risk that a common cancer will occur in relatives of an
affected person is generally low, but familial aggregations that
cannot be explained by environmental factors alone exist for
some neoplasms. Up to 5% of cases of breast, ovary, and bowel
cancers are inherited because of mutations in incompletely
penetrant, autosomal dominant genes. There are also several
cancer predisposing syndromes that are inherited in a
mendelian fashion, and the genes responsible for many of
these have been cloned.
affected person is generally low, but familial aggregations that
cannot be explained by environmental factors alone exist for
some neoplasms. Up to 5% of cases of breast, ovary, and bowel
cancers are inherited because of mutations in incompletely
penetrant, autosomal dominant genes. There are also several
cancer predisposing syndromes that are inherited in a
mendelian fashion, and the genes responsible for many of
these have been cloned.
Mechanisms of tumorigenesis
The genetic basis of both sporadic and inherited cancers has
been confirmed by molecular studies. The three main classes of
genes known to predispose to malignancy are oncogenes,
tumour suppressor genes and genes involved in DNA mismatch
repair. In addition, specific mutagenic defects from
environmental carcinogens and viral infections (notably
hepatitis B) have been identified.
been confirmed by molecular studies. The three main classes of
genes known to predispose to malignancy are oncogenes,
tumour suppressor genes and genes involved in DNA mismatch
repair. In addition, specific mutagenic defects from
environmental carcinogens and viral infections (notably
hepatitis B) have been identified.
Oncogene
Oncogenes are genes that can cause malignant
transformation of normal cells. They were first recognised as
viral oncogenes (v-onc) carried by RNA viruses. These
retroviruses incorporate a DNA copy of their genomic RNA
into host DNA and cause neoplasia in animals. Sequences
homologous to those of viral oncogenes were subsequently
detected in the human genome and called cellular oncogenes
(c-onc). Numerous proto-oncogenes have now been identified,
whose normal function is to promote cell growth and
differentiation. Mutation in a proto-oncogene results in altered,
enhanced, or inappropriate expression of the gene product
leading to neoplasia. Oncogenes act in a dominant fashion in
tumour cells, i.e. mutation in one copy of the gene is sufficient
to cause neoplasia. Proto-oncogenes may be activated by point
mutations, but also by mutations that do not alter the coding
sequence, such as gene amplification or chromosomal
translocation. Most proto-oncogene mutations occur at a
somatic level, causing sporadic cancers. Exceptions include the
germline mutation in the RET oncogene responsible for
dominantly inherited multiple endocrine neoplasia type II.
transformation of normal cells. They were first recognised as
viral oncogenes (v-onc) carried by RNA viruses. These
retroviruses incorporate a DNA copy of their genomic RNA
into host DNA and cause neoplasia in animals. Sequences
homologous to those of viral oncogenes were subsequently
detected in the human genome and called cellular oncogenes
(c-onc). Numerous proto-oncogenes have now been identified,
whose normal function is to promote cell growth and
differentiation. Mutation in a proto-oncogene results in altered,
enhanced, or inappropriate expression of the gene product
leading to neoplasia. Oncogenes act in a dominant fashion in
tumour cells, i.e. mutation in one copy of the gene is sufficient
to cause neoplasia. Proto-oncogenes may be activated by point
mutations, but also by mutations that do not alter the coding
sequence, such as gene amplification or chromosomal
translocation. Most proto-oncogene mutations occur at a
somatic level, causing sporadic cancers. Exceptions include the
germline mutation in the RET oncogene responsible for
dominantly inherited multiple endocrine neoplasia type II.
Tumour suppressor genes
Tumour suppressor genes normally act to inhibit cell
proliferation by stopping cell division, initiating apoptosis (cell
death) or being involved in DNA repair mechanisms. Loss of
function or inactivation of these genes is associated with
tumorigenesis. At the cellular level these genes act in a
recessive fashion, as loss of activity of both copies of the gene is
required for malignancy to develop. Mutations inactivating
various tumour suppressor genes are found in both sporadic
and hereditary cancers.
proliferation by stopping cell division, initiating apoptosis (cell
death) or being involved in DNA repair mechanisms. Loss of
function or inactivation of these genes is associated with
tumorigenesis. At the cellular level these genes act in a
recessive fashion, as loss of activity of both copies of the gene is
required for malignancy to develop. Mutations inactivating
various tumour suppressor genes are found in both sporadic
and hereditary cancers.
tumour development is the failure to repair damaged DNA
Another mechanism for tumour development is the failure
to repair damaged DNA. Xeroderma pigmentosum, for
example, is a rare autosomal recessive disorder caused by
failure to repair DNA damaged by ultraviolet light. Exposure to
sunlight causes multiple skin tumours in affected individuals.
Many other tumours are found to be associated with instability
of multiple microsatellite markers because of a failure to repair
mutated DNA containing mismatched base pairs. Microsatellite
instability is particularly common in colorectal, gastric and
endometrial cancers. Hereditary non-polyposis colon cancer
(HNPCC) is due to mutations in genes on chromosomes 2p,
2q, 3p and 7p. The hMSH2 gene on chromosome 2p represents
a mismatch repair gene. Some patients with HNPCC inherit
one mutant copy of this gene, which is inactivated in all cells.
Loss of the other allele (loss of heterozygosity) in colonic cells
leads to an increase in the mutation rate in other genes,
resulting in the development of colonic cancer.
to repair damaged DNA. Xeroderma pigmentosum, for
example, is a rare autosomal recessive disorder caused by
failure to repair DNA damaged by ultraviolet light. Exposure to
sunlight causes multiple skin tumours in affected individuals.
Many other tumours are found to be associated with instability
of multiple microsatellite markers because of a failure to repair
mutated DNA containing mismatched base pairs. Microsatellite
instability is particularly common in colorectal, gastric and
endometrial cancers. Hereditary non-polyposis colon cancer
(HNPCC) is due to mutations in genes on chromosomes 2p,
2q, 3p and 7p. The hMSH2 gene on chromosome 2p represents
a mismatch repair gene. Some patients with HNPCC inherit
one mutant copy of this gene, which is inactivated in all cells.
Loss of the other allele (loss of heterozygosity) in colonic cells
leads to an increase in the mutation rate in other genes,
resulting in the development of colonic cancer.
gene in human cancers
The most commonly altered gene in human cancers is the
tumour suppressor gene TP53 which encodes the p53 protein.
TP53 mutations are found in about 70% of all tumours.
Mutations in the RAS oncogene occur in about one third.
Interestingly, somatic mutations in the tumour suppressor gene
TP53 are often found in sporadic carcinoma of the colon, but
germline mutation of TP53 (responsible for Li–Fraumeni
syndrome) seldom predisposes to colonic cancer. Similarly,
lung cancers often show somatic mutations of the
retinoblastoma (RB1) gene, but this tumour does not occur in
individuals who inherit germline RB1 mutations. These genes
probably play a greater role in progression, than in initiation,
of these tumours. Although caused by mutations in the hMSH2
gene, the colonic cancers commonly associated with HNPCC
show somatic mutations similar to those found in sporadic
colon cancers, that is in the adenomatous polyposis coli (APC)
gene, K-RAS oncogene and TP53 tumour suppressor. This is
because the HNPCC predisposing mismatch repair genes are
acting as mutagenic rather than tumour suppressor genes.
tumour suppressor gene TP53 which encodes the p53 protein.
TP53 mutations are found in about 70% of all tumours.
Mutations in the RAS oncogene occur in about one third.
Interestingly, somatic mutations in the tumour suppressor gene
TP53 are often found in sporadic carcinoma of the colon, but
germline mutation of TP53 (responsible for Li–Fraumeni
syndrome) seldom predisposes to colonic cancer. Similarly,
lung cancers often show somatic mutations of the
retinoblastoma (RB1) gene, but this tumour does not occur in
individuals who inherit germline RB1 mutations. These genes
probably play a greater role in progression, than in initiation,
of these tumours. Although caused by mutations in the hMSH2
gene, the colonic cancers commonly associated with HNPCC
show somatic mutations similar to those found in sporadic
colon cancers, that is in the adenomatous polyposis coli (APC)
gene, K-RAS oncogene and TP53 tumour suppressor. This is
because the HNPCC predisposing mismatch repair genes are
acting as mutagenic rather than tumour suppressor genes.
gene therapy for cancers
There now exists the possibility of gene therapy for cancers,
and many of the protocols currently approved for genetic
therapy are for patients with cancer. Several approaches are
being investigated, including virally directed enzyme prodrug
therapy, the use of transduced tumour infiltrating lymphocytes,
which produce toxic gene products, modifying tumour
immunogenicity by inserting genes, or the direct manipulation
of crucial oncogenes or tumour suppressor genes.
and many of the protocols currently approved for genetic
therapy are for patients with cancer. Several approaches are
being investigated, including virally directed enzyme prodrug
therapy, the use of transduced tumour infiltrating lymphocytes,
which produce toxic gene products, modifying tumour
immunogenicity by inserting genes, or the direct manipulation
of crucial oncogenes or tumour suppressor genes.
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