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Genetics of disease
Genetics of disease Editorial overview Peter N Goodfellow*
Camerinoi
In
Addresses ‘SmithKline
Beecham
Third Avenue,
Harlow,
Pharmaceuticals,
New Frontiers
Essex CM1 9 5AW,
+Biologia Generale e Genetica Medica, Forlanini 14, 27100 Pavia, Italy Current
and Giovanna
Opinion
in Genetics
Science
Park,
UK
Universita
& Development
di Pavia, via
1997, 7:329-330
previous
issues,
we
have
emphasised
both
single
genes causing specific diseases and collections of genes causing related diseases, such as the muscular dystrophies. However, just as there are many ways of displaying human artefacts, there are many other ways to group together genes,
including:
http://biomednet.com/elecref/0959437X00700329 0 Current
Biology
Ltd ISSN 0959-437X
1. Biochemical
function.
Abbreviations AMH HMG FGF TGF-P
anti-Miillerian high mobility
hormone group
2. Physiological
fibroblast growth factor transforming growth factor-p
3. Structure
Commissioning and organising an issue of Current Opinion in Genetics ad Development is an enjoyable task; however, it is not always easy. The Human Genome Project and the recent emphasis on DNA sequencing have led to an exponential increase in the rate of gene identification-making it hard to cover all the new advances. In addition, a carefully crafted collection of essays can be disrupted either by reviews that do not appear or by recent advances that make all but today’s journals out of date. This can leave the Editors with the difficult task of explaining why the underlying philosophy of their
issue
Perhaps
the
is hard to discern. best
place
to
start
our
apologia
is
the
Pitt Rivers Museum in Oxford. Modern ethnologists, anthropologists and museum curators have agreed that artefacts in museums should be arranged according to their cultural origins. This allows a glimpse of how other cultures functioned and, by comparison, how our own society works. This is not the only way to organise a museum, however, the great Victorian collectors were more interested in specific objects than whole societies.
The Pitt Rivers Museum is named after its benefactor, who stipulated that the objects should be displayed according to their social use. Implements for grooming hair are found in one cabinet and tools for cutting beards are in the next cabinet. Sea shells, metal discs, and feathers are placed together because they have all been used as currency. Sometimes the grouped items are related not only by function but also by direct relationship where one culture has learned from and adapted the artefacts of another. Sometimes the articles have been invented and re-invented completely independently.
role.
of encoded
4. Expression
patterns.
5. Subcellular
location
6. Evolutionary
7. Species
origin
proteins.
of encoded
protein.
(i.e. homology).
of origin.
In this issue, we have attempted a slightly different approach from before: we have concentrated on reviews of gene families. The reasons for this are two-fold. First, there have been such a number of cloned genes that have a medical relevance that a gene-by-gene approach is no longer possible. Second, members of the same gene family tend to have similar biochemistry and physiology and are, by definition, homologous. By comparing the properties of members of the same gene family, it may be possible to make predictions about new members which are soon to be discovered.
The
HOX
genes,
reviewed
by Boncinelli
(pp
331-337),
encode proteins that include a DNA-binding ‘homeodomain’. These proteins are regulatory factors known to control gene expression during development. Recent work has also shown that some members of the family are able to bind to RNA. Given the central role of HOX genes in developmental regulation, it is perhaps surprising that few diseases have been associated with mutations in these genes. This situation is beginning to change; HOXD13, has been implicated in synpolydactyly and E,MXZ is mutated in schizencephaly. The SOX genes were named after SRY, the founding member of the family (after SRY box). Those that named the family hoped that the name assonance with HOX genes would lead to fame and glory, even though
330
Genetics of disease
the DNA-binding ‘box’ is a subfamily of the HhlG-box and unrelated to the homeodomain of HOX genes. Pevny
receptor genes can cause diseases dwarfism and craniosynostosis.
and Lovell-Badge (pp 338-344) describe implicate the SOX genes in developmental
Skeletal
the choice
the data which regulation and
of cell fate.
Control of gene expression at the level of transcription received more attention than the post-transcriptional, translational
and
post-translational
levels.
This
focus
has
is
partly because of the available tools and is not necessarily a reflection of biological importance. The family of proteins that bind mRNA is poorly defined and heterogeneous (Siomi and Dreyfuss [pp 345-3531) but the amplification of biological complexity inherent in alternative splicing and alternative sites for translation initiation must be crucial for gene regulation. Defining the cis RNA signals and the tmns proteins that recognise them is an important challenge. Another class of proteins that bind to nucleic acids are the helicases. Fourteen DNA helicases and seventeen RNA helicases are known in humans (Ellis [pp 354-3631) and it is likely that many remain undiscovered. hlutations in DNA helicase genes can cause complex and diverse diseases, including syndromes with cancer prediposition and UV sensitivity. Cancer pedisposition is also a feature of mutations in the DNA mismatch repair system (Arnheim and Shibata [pp 364-3701). Although the genes involved are not members of a gene family, the system has been strongly conserved in evolution and studies in Eschricha co/i and yeast have been instrumental in understanding the causes of hereditary nonpolyposis colorectal cancer. The
cell surface.is
the organelle
through
which
the cell
receives information about its environment. Signalling at surface receptors is crucial for determining cell responses and the integration of cell behaviour in tissues. Two reviews cover different cell surface receptors. Josso and di Clemente (pp 371-377) describe the serine/threonine kinase receptors and their ligands. Most cell surface serine/threonine kinases are receptors for members of the TGF-B growth factor family. Included in this ligand family is AMH (anti-Miillerian hormone) which is responsible for Miillerian duct regression. It is reassuring that the phenotypes of individuals with mutations either in AMH or in the receptor are identical. The receptors for fibroblast growth factors are tyrosine kinases (De Moerlooze and Dickson [pp 378-3851). Mutations in three different FGF
effects
are also seen
of the skeleton
in X-linked
including
chondrodysplasia
punctata but the underlying defect is not in signalling but in the enzyme arylsulfatase E (Parenti eta/. [pp 386-3911). The sulfatases share a common biochemical role in catalysing the hydrolysis of sulphate ester bonds from different substrates. For enzymic activity, the sulfatases are modified by a post translational mechanism to replace an active-site cysteine by a Z-amino-3-oxopropionic acid or serine defective
semialdehyde. This modification in the rare disease multiple sulfatase
system is deficiency.
As the various genome sequencing projects develop, new gene families will be defined. One recent example of an ‘emerging’ family is the plakins (Ruhrberg and Watt [pp 392-3971). This family is composed of genes that encode four proteins (desmoplakin, plectin, BPAGl and envoplakin) all of which are found at filament and intermediate filament attachment sites. hlutations in plakin genes can cause both skin disease and neurodegeneration. Genetics offers promise for understanding the basis of the complex common diseases which are the cause of morbidity and mortality in the western world. Obesity is a disease which has serious health affects not least being the co-morbid diseases diabetes and hypertension. The major advances in this area have not come from studying the complex human disease directly but from the cloning of five different monogenic disease genes in the mouse (Naggert eta/. [pp 398-404]). This is not the first time that the mouse has proved to be essential for understanding disease biology and it will be even more powerful when we have access to mouse expressed sequence tags (ESTs) and genomic sequence. The value of genomic sequence for comparative biology has already been proven by studies in yeast (Oliver [pp 4054091) and the nematode (Ahringer [pp 410-415]). Analysis of these organisms is providing a paradigm for when the complete human and mouse genome sequences become available. Whatever the outcome, it is obvious that we will need better computational tools and that bioinformatics will grow to become a dominant in biology (Rawlings and Searls [pp 416~+23]).
discipline
Camerinoi
In
Addresses ‘SmithKline
Beecham
Third Avenue,
Harlow,
Pharmaceuticals,
New Frontiers
Essex CM1 9 5AW,
+Biologia Generale e Genetica Medica, Forlanini 14, 27100 Pavia, Italy Current
and Giovanna
Opinion
in Genetics
Science
Park,
UK
Universita
& Development
di Pavia, via
1997, 7:329-330
previous
issues,
we
have
emphasised
both
single
genes causing specific diseases and collections of genes causing related diseases, such as the muscular dystrophies. However, just as there are many ways of displaying human artefacts, there are many other ways to group together genes,
including:
http://biomednet.com/elecref/0959437X00700329 0 Current
Biology
Ltd ISSN 0959-437X
1. Biochemical
function.
Abbreviations AMH HMG FGF TGF-P
anti-Miillerian high mobility
hormone group
2. Physiological
fibroblast growth factor transforming growth factor-p
3. Structure
Commissioning and organising an issue of Current Opinion in Genetics ad Development is an enjoyable task; however, it is not always easy. The Human Genome Project and the recent emphasis on DNA sequencing have led to an exponential increase in the rate of gene identification-making it hard to cover all the new advances. In addition, a carefully crafted collection of essays can be disrupted either by reviews that do not appear or by recent advances that make all but today’s journals out of date. This can leave the Editors with the difficult task of explaining why the underlying philosophy of their
issue
Perhaps
the
is hard to discern. best
place
to
start
our
apologia
is
the
Pitt Rivers Museum in Oxford. Modern ethnologists, anthropologists and museum curators have agreed that artefacts in museums should be arranged according to their cultural origins. This allows a glimpse of how other cultures functioned and, by comparison, how our own society works. This is not the only way to organise a museum, however, the great Victorian collectors were more interested in specific objects than whole societies.
The Pitt Rivers Museum is named after its benefactor, who stipulated that the objects should be displayed according to their social use. Implements for grooming hair are found in one cabinet and tools for cutting beards are in the next cabinet. Sea shells, metal discs, and feathers are placed together because they have all been used as currency. Sometimes the grouped items are related not only by function but also by direct relationship where one culture has learned from and adapted the artefacts of another. Sometimes the articles have been invented and re-invented completely independently.
role.
of encoded
4. Expression
patterns.
5. Subcellular
location
6. Evolutionary
7. Species
origin
proteins.
of encoded
protein.
(i.e. homology).
of origin.
In this issue, we have attempted a slightly different approach from before: we have concentrated on reviews of gene families. The reasons for this are two-fold. First, there have been such a number of cloned genes that have a medical relevance that a gene-by-gene approach is no longer possible. Second, members of the same gene family tend to have similar biochemistry and physiology and are, by definition, homologous. By comparing the properties of members of the same gene family, it may be possible to make predictions about new members which are soon to be discovered.
The
HOX
genes,
reviewed
by Boncinelli
(pp
331-337),
encode proteins that include a DNA-binding ‘homeodomain’. These proteins are regulatory factors known to control gene expression during development. Recent work has also shown that some members of the family are able to bind to RNA. Given the central role of HOX genes in developmental regulation, it is perhaps surprising that few diseases have been associated with mutations in these genes. This situation is beginning to change; HOXD13, has been implicated in synpolydactyly and E,MXZ is mutated in schizencephaly. The SOX genes were named after SRY, the founding member of the family (after SRY box). Those that named the family hoped that the name assonance with HOX genes would lead to fame and glory, even though
330
Genetics of disease
the DNA-binding ‘box’ is a subfamily of the HhlG-box and unrelated to the homeodomain of HOX genes. Pevny
receptor genes can cause diseases dwarfism and craniosynostosis.
and Lovell-Badge (pp 338-344) describe implicate the SOX genes in developmental
Skeletal
the choice
the data which regulation and
of cell fate.
Control of gene expression at the level of transcription received more attention than the post-transcriptional, translational
and
post-translational
levels.
This
focus
has
is
partly because of the available tools and is not necessarily a reflection of biological importance. The family of proteins that bind mRNA is poorly defined and heterogeneous (Siomi and Dreyfuss [pp 345-3531) but the amplification of biological complexity inherent in alternative splicing and alternative sites for translation initiation must be crucial for gene regulation. Defining the cis RNA signals and the tmns proteins that recognise them is an important challenge. Another class of proteins that bind to nucleic acids are the helicases. Fourteen DNA helicases and seventeen RNA helicases are known in humans (Ellis [pp 354-3631) and it is likely that many remain undiscovered. hlutations in DNA helicase genes can cause complex and diverse diseases, including syndromes with cancer prediposition and UV sensitivity. Cancer pedisposition is also a feature of mutations in the DNA mismatch repair system (Arnheim and Shibata [pp 364-3701). Although the genes involved are not members of a gene family, the system has been strongly conserved in evolution and studies in Eschricha co/i and yeast have been instrumental in understanding the causes of hereditary nonpolyposis colorectal cancer. The
cell surface.is
the organelle
through
which
the cell
receives information about its environment. Signalling at surface receptors is crucial for determining cell responses and the integration of cell behaviour in tissues. Two reviews cover different cell surface receptors. Josso and di Clemente (pp 371-377) describe the serine/threonine kinase receptors and their ligands. Most cell surface serine/threonine kinases are receptors for members of the TGF-B growth factor family. Included in this ligand family is AMH (anti-Miillerian hormone) which is responsible for Miillerian duct regression. It is reassuring that the phenotypes of individuals with mutations either in AMH or in the receptor are identical. The receptors for fibroblast growth factors are tyrosine kinases (De Moerlooze and Dickson [pp 378-3851). Mutations in three different FGF
effects
are also seen
of the skeleton
in X-linked
including
chondrodysplasia
punctata but the underlying defect is not in signalling but in the enzyme arylsulfatase E (Parenti eta/. [pp 386-3911). The sulfatases share a common biochemical role in catalysing the hydrolysis of sulphate ester bonds from different substrates. For enzymic activity, the sulfatases are modified by a post translational mechanism to replace an active-site cysteine by a Z-amino-3-oxopropionic acid or serine defective
semialdehyde. This modification in the rare disease multiple sulfatase
system is deficiency.
As the various genome sequencing projects develop, new gene families will be defined. One recent example of an ‘emerging’ family is the plakins (Ruhrberg and Watt [pp 392-3971). This family is composed of genes that encode four proteins (desmoplakin, plectin, BPAGl and envoplakin) all of which are found at filament and intermediate filament attachment sites. hlutations in plakin genes can cause both skin disease and neurodegeneration. Genetics offers promise for understanding the basis of the complex common diseases which are the cause of morbidity and mortality in the western world. Obesity is a disease which has serious health affects not least being the co-morbid diseases diabetes and hypertension. The major advances in this area have not come from studying the complex human disease directly but from the cloning of five different monogenic disease genes in the mouse (Naggert eta/. [pp 398-404]). This is not the first time that the mouse has proved to be essential for understanding disease biology and it will be even more powerful when we have access to mouse expressed sequence tags (ESTs) and genomic sequence. The value of genomic sequence for comparative biology has already been proven by studies in yeast (Oliver [pp 4054091) and the nematode (Ahringer [pp 410-415]). Analysis of these organisms is providing a paradigm for when the complete human and mouse genome sequences become available. Whatever the outcome, it is obvious that we will need better computational tools and that bioinformatics will grow to become a dominant in biology (Rawlings and Searls [pp 416~+23]).
discipline