Medical Genetics
12 多基因遗传疾病
Polygenetic disorders
Medical Genetics
Medical Genetics
1,schizophrenia,SP
Schizophrenia is a humorous
brain disorder characterized by
delusional thinking and unique but
unpopular perceptions,
Medical Genetics
Mental health professionals normally
diagnose this illness if,during any one-
month period of a person’s life,that
person has suffered two or more of the
following,
Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms
Medical Genetics
Negative symptoms are the most
insidious behavioral effects of
schizophrenia,They can include low levels
of,
Interest
Motivation
Emotional arousal
Mental activity
Social drive
Speech
Medical Genetics
Schizophrenia is equally represented
in women and men,The onset of the
illness generally occurs at a later age in
women than in men (between ages 23 and
35 in women versus 18 to 25 for men),
Not only do women generally present with
schizophrenia at later ages,but the
phenomenon of late onset schizophrenia
(40+ years) is almost entirely a female
one,
Medical Genetics
Medical Genetics
Women tend to display more prominent
mood symptoms and men more negative
symptoms,In the first episode of
schizophrenia,women are more likely to
display intense irritability,anger,and
sadness; men are more likely to be
withdrawn and emotionally apathetic,
After the first episode,these distinctions
begin to blur,PMS is not an indication of
the onset of schizophrenia in women,
although the symptoms are strikingly
similar,
Medical Genetics
Subtypes of Schizophrenia
1,Disorganized Type
2,Catatonic Type
3,Paranoid Type
4,Undifferentiated Type
5,Residual Type
Medical Genetics
Disorganized Type
This subtype of schizophrenia is
marked by significant regression to
primitive,uninhibited,and disorganized
behavior,Thumb-sucking,howling like a
wolf,temper tantrums,creation of
pornographic art and unreasonably
strong cravings to suckle a female’s
breast are characteristic of this type,
Medical Genetics
Catatonic Type
This subtype features gross
psychomotor disturbances,i.e.,stupor,
negativism,mutism,rigidity,excitement,
prolonged erection,or posturing,Frequent
fluctuation between these extreme physical
states is common,Schizophrenics of this type
can be the most fun for psychologists to play
with,They can be posed like dolls,undressed
while they’re catatonic and then left in a
crowded bus station to regain psychomotor
normality,or even substituted for psychiatrists
in therapy sessions,
Medical Genetics
Paranoid Type
More often than not,this is a misdiagnosed
condition of prominent delusions or auditory
hallucinations of persecution or grandeur,
accompanied by a relative preservation of
cognitive functioning,In reality,these are
functionally normal individuals who have
discovered the fact that some other individual
or organization is conspiring or acting to
torture,murder,or financially disable them,
but are unable to produce legitimate evidence
supporting their suspicions,
Medical Genetics
Undifferentiated Type
This type was originally designed as a
catch-all category for psychiatrists and
psychologists too incompetent to diagnose a
schizophrenic’s specific type,It is allegedly
used when patients do not clearly fit into any
one type,fit into more than one type,or do
not fit into any of the other types,Psychiatrists
tend to categorize schizophrenics as
undifferentiated pending the discovery or
creation of new mental disorders to label them
with,
Medical Genetics
Residual Type
This type commonly displays
emotional bluntness,social withdrawal,
illogical thinking,eccentric behavior,or
mild loosening of association,Elderly
people suffering from Alzheimer’s
disease,lepers,philosophers and
Japanese males who have,lost face” are
characteristic of this type,
Medical Genetics
Causes of schizophrenia
The cause of schizophrenia is
unknown,Many mental health
professionals believe there are
factors which increase an individual’s
risk of having schizophrenia,
Medical Genetics
For example,first-degree
biological relatives of persons with
schizophrenia have a ten times
greater risk of developing the illness
than members of the general
population,Also,in the United States,
more schizophrenic patients are born
in the winter months of January to
April,
Medical Genetics
Medical Genetics
Medical Genetics
Exhaustive scientific studies have
revealed that mental health
professionals who subscribe to this
theory of causality also believe
astrology is a legitimate scientific
field,
Medical Genetics
Because there is no cure for
schizophrenia,the goal of treatment
is to eliminate or reduce symptoms,
minimize side effects,prevent
relapse,and socially and
occupationally rehabilitate the
patient,
Medical Genetics
This process can last a lifetime,
or at least as long as a patient has
available funds to pay for therapy,
When funds are exhausted,mental
health professionals generally begin
advising their patients of the
schizophrenic likelihood of suicide,
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
2,diabetes mellitus
The term diabetes mellitus
describes a metabolic disorder of
multiple aetiology characterized by
chronic hyperglycaemia with
disturbances of carbohydrate,fat
and protein metabolism resulting
from defects in insulin secretion,
insulin action,or both,
Medical Genetics
Medical Genetics
Medical Genetics
The effects of diabetes mellitus
include long-term damage,dysfunction
and failure of various organs,Diabetes
mellitus may present with characteristic
symptoms such as thirst,polyuria,
blurring of vision,and weight loss,In its
most severe forms,ketoacidosis or a non-
ketotic hyperosmolar state may develop
and lead to stupor,coma and,in absence
of effective treatment,death,
Medical Genetics
Often symptoms are not severe,
or may be absent,and consequently
hyperglycaemia sufficient to cause
pathological and functional changes
may be present for a long time
before the diagnosis is made,
Medical Genetics
The long-term effects of diabetes
mellitus include progressive development
of the specific complications of retinopathy
with potential blindness,nephropathy that
may lead to renal failure,and/or
neuropathy with risk of foot ulcers,
amputation,Charcot joints,and features
of autonomic dysfunction,including sexual
dysfunction,People with diabetes are at
increased risk of cardiovascular,peripheral
vascular and cerebrovascular disease,
Medical Genetics
Several pathogenetic processes are
involved in the development of diabetes,
These include processes which destroy the
beta cells of the pancreas with consequent
insulin deficiency,and others that result in
resistance to insulin action,The
abnormalities of carbohydrate,fat and
protein metabolism are due to deficient
action of insulin on target tissues resulting
from insensitivity or lack of insulin,
Medical Genetics
Aetiological Classification of Disorders of Glycaemia
? Type 1, (beta-cell destruction,usually leading to
absolute insulin deficiency)
– Autoimmune
– Idiopathic
? Type 2, (may range from predominantly insulin
resistance with relative insulin deficiency to a
predominantly secretory defect with or without
insulin resistance)
? Other specific types
– Genetic defects of beta-cell function
– Genetic defects in insulin action
– Diseases of the exocrine pancreas
– Endocrinopathies
– Drug- or chemical-induced
– Infections
– Uncommon forms of immune-mediated diabetes
– Other genetic syndromes sometimes associated with diabetes
? Gestational diabetes
Medical Genetics
Genetic defects
Several forms of the diabetic state may be
associated with monogenic defects in beta-cell
function,frequently characterized by onset of
mild hyperglycaemia at an early age (generally
before age 25 years),They are usually inherited
in an autosomal dominant pattern,Patients with
these forms of diabetes,formerly referred to as
maturity-onset diabetes of the young (MODY),
have impaired insulin secretion with minimal or
no defect in insulin action,
Medical Genetics
Abnormalities at several genetic
loci on different chromosomes have
now been characterized,
Medical Genetics
The most common form is
associated with mutations on
chromosome 12 in a hepatic nuclear
transcription factor referred to as
HNF1alpha,
Medical Genetics
A second form is associated
with mutations in the glucokinase
gene on chromosome 7p,
Glucokinase converts glucose to
glucose-6-phosphate,the
metabolism of which in turn
stimulates insulin secretion by the
beta cell,
Medical Genetics
Thus,glucokinase serves as the
"glucose sensor" for the beta cell,
Because of defects in the glucokinase
gene,increased levels of glucose are
necessary to elicit normal levels of
insulin secretion,
Medical Genetics
A third form is associated with
a mutation in the HNF4alpha gene on
chromosome 20q, HNF4alpha is a
transcription factor which is involved
in the regulation of the expression of
HNF1alpha,
Medical Genetics
A fourth variant has recently
been ascribed to mutations in
another transcription factor gene,
IPF-1,which in its homozygous form
leads to total pancreatic agenesis,
Medical Genetics
Specific genetic defects in other
individuals who have a similar clinical
presentation are currently being
defined,
Medical Genetics
Point mutations in
mitochondrial DNA have been found
to be associated with diabetes
mellitus and deafness, The most
common mutation occurs at position
3243 in the tRNA leucine gene,
leading to an A to G substitution,
Medical Genetics
An identical lesion occurs in the
MELAS syndrome (Mitochondrial
myopathy,Encephalopathy,Lactic
Acidosis,and Stroke-like syndrome);
however,diabetes is not part of this
syndrome,suggesting for unknown
reasons different phenotypic
expressions of this genetic lesion,
Medical Genetics
3,bronchial asthma
Bronchial asthma is the more correct
name for the common form of asthma,
The term bronchial asthma is used to
differentiate it from cardiac asthma,
Although the two types of asthma have
similar symptoms,including shortness of
breath and wheezing (a whistling sound in
the chest),they have quite different
causes,
Medical Genetics
For most people with bronchial
asthma,the pattern is periodic
attacks of wheezing alternating with
periods of quite normal breathing,
However,some people with bronchial
asthma alternate between chronic
shortness of breath and episodes of
even worse shortness of breath,
Medical Genetics
Strong risks for developing
bronchial asthma include being a
person who is genetically susceptible
to asthma and being exposed early
in life to indoor allergens,such as
dust mites and cockroaches,and
having a family history of asthma or
allergy,
Medical Genetics
Medical Genetics
Bronchial asthma attacks can be triggered
(precipitated or aggravated) by various
factors,including,
? respiratory tract infections;
? cold weather;
? exercise;
? cigarette smoke and other air pollutants;
? stress,
Medical Genetics
In sensitive individuals,asthma
symptoms can be triggered by inhaled
allergens (allergy triggers),such as pet
dander,dust mites,cockroach allergens,
molds,or pollens,Asthma symptoms can
also be triggered by respiratory infections,
exercise,cold air,tobacco smoke and
other pollutants,stress,food,or drug
allergies,
Medical Genetics
The symptoms of bronchial asthma
include,
? a feeling of tightness in the chest;
? difficulty in breathing or shortness of
breath;
? wheezing; and
? coughing (particularly at night),
Medical Genetics
Medical Genetics
Asthma is found in 3-5% of
adults and 7-10% of children,Half of
the people with asthma develop it
before age 10,and most develop it
before age 30,Asthma symptoms
can decrease over time,especially in
children,
Medical Genetics
Gene-environment interactions in
the early life origins of asthma
Medical Genetics
Genetic and Molecular Regulation of
ADAM33
ADAM33 was the first asthma
susceptibility gene identified as a result of
a genome-wide positional cloning effort,
The identification of ADAM33 as a major
risk factor involved in the pathogenesis of
bronchial hyper-responsiveness (BHR) and
airway wall remodeling provides insight
into the pathogenesis of asthma and
represents a novel therapeutic target,
Medical Genetics
The occurrence of ADAM33 in embryonic mesenchymal
cells suggests that it may be involved in airway wall
"modeling" that contributes to the early life origins of
asthma,We are conducting further studies into the genetic
and molecular regulation of ADAM33 including,
? Characterisation of the ADAM33 promoter
? Correlation of ADAM33 genotypes/haplotypes with
molecular phenotypes
? Association of ADAM33 polymorphism with early-life lung
function and COPD susceptibility
? ADAM33-environment interactions and asthma
susceptibility
12 多基因遗传疾病
Polygenetic disorders
Medical Genetics
Medical Genetics
1,schizophrenia,SP
Schizophrenia is a humorous
brain disorder characterized by
delusional thinking and unique but
unpopular perceptions,
Medical Genetics
Mental health professionals normally
diagnose this illness if,during any one-
month period of a person’s life,that
person has suffered two or more of the
following,
Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic behavior
Negative symptoms
Medical Genetics
Negative symptoms are the most
insidious behavioral effects of
schizophrenia,They can include low levels
of,
Interest
Motivation
Emotional arousal
Mental activity
Social drive
Speech
Medical Genetics
Schizophrenia is equally represented
in women and men,The onset of the
illness generally occurs at a later age in
women than in men (between ages 23 and
35 in women versus 18 to 25 for men),
Not only do women generally present with
schizophrenia at later ages,but the
phenomenon of late onset schizophrenia
(40+ years) is almost entirely a female
one,
Medical Genetics
Medical Genetics
Women tend to display more prominent
mood symptoms and men more negative
symptoms,In the first episode of
schizophrenia,women are more likely to
display intense irritability,anger,and
sadness; men are more likely to be
withdrawn and emotionally apathetic,
After the first episode,these distinctions
begin to blur,PMS is not an indication of
the onset of schizophrenia in women,
although the symptoms are strikingly
similar,
Medical Genetics
Subtypes of Schizophrenia
1,Disorganized Type
2,Catatonic Type
3,Paranoid Type
4,Undifferentiated Type
5,Residual Type
Medical Genetics
Disorganized Type
This subtype of schizophrenia is
marked by significant regression to
primitive,uninhibited,and disorganized
behavior,Thumb-sucking,howling like a
wolf,temper tantrums,creation of
pornographic art and unreasonably
strong cravings to suckle a female’s
breast are characteristic of this type,
Medical Genetics
Catatonic Type
This subtype features gross
psychomotor disturbances,i.e.,stupor,
negativism,mutism,rigidity,excitement,
prolonged erection,or posturing,Frequent
fluctuation between these extreme physical
states is common,Schizophrenics of this type
can be the most fun for psychologists to play
with,They can be posed like dolls,undressed
while they’re catatonic and then left in a
crowded bus station to regain psychomotor
normality,or even substituted for psychiatrists
in therapy sessions,
Medical Genetics
Paranoid Type
More often than not,this is a misdiagnosed
condition of prominent delusions or auditory
hallucinations of persecution or grandeur,
accompanied by a relative preservation of
cognitive functioning,In reality,these are
functionally normal individuals who have
discovered the fact that some other individual
or organization is conspiring or acting to
torture,murder,or financially disable them,
but are unable to produce legitimate evidence
supporting their suspicions,
Medical Genetics
Undifferentiated Type
This type was originally designed as a
catch-all category for psychiatrists and
psychologists too incompetent to diagnose a
schizophrenic’s specific type,It is allegedly
used when patients do not clearly fit into any
one type,fit into more than one type,or do
not fit into any of the other types,Psychiatrists
tend to categorize schizophrenics as
undifferentiated pending the discovery or
creation of new mental disorders to label them
with,
Medical Genetics
Residual Type
This type commonly displays
emotional bluntness,social withdrawal,
illogical thinking,eccentric behavior,or
mild loosening of association,Elderly
people suffering from Alzheimer’s
disease,lepers,philosophers and
Japanese males who have,lost face” are
characteristic of this type,
Medical Genetics
Causes of schizophrenia
The cause of schizophrenia is
unknown,Many mental health
professionals believe there are
factors which increase an individual’s
risk of having schizophrenia,
Medical Genetics
For example,first-degree
biological relatives of persons with
schizophrenia have a ten times
greater risk of developing the illness
than members of the general
population,Also,in the United States,
more schizophrenic patients are born
in the winter months of January to
April,
Medical Genetics
Medical Genetics
Medical Genetics
Exhaustive scientific studies have
revealed that mental health
professionals who subscribe to this
theory of causality also believe
astrology is a legitimate scientific
field,
Medical Genetics
Because there is no cure for
schizophrenia,the goal of treatment
is to eliminate or reduce symptoms,
minimize side effects,prevent
relapse,and socially and
occupationally rehabilitate the
patient,
Medical Genetics
This process can last a lifetime,
or at least as long as a patient has
available funds to pay for therapy,
When funds are exhausted,mental
health professionals generally begin
advising their patients of the
schizophrenic likelihood of suicide,
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
Medical Genetics
2,diabetes mellitus
The term diabetes mellitus
describes a metabolic disorder of
multiple aetiology characterized by
chronic hyperglycaemia with
disturbances of carbohydrate,fat
and protein metabolism resulting
from defects in insulin secretion,
insulin action,or both,
Medical Genetics
Medical Genetics
Medical Genetics
The effects of diabetes mellitus
include long-term damage,dysfunction
and failure of various organs,Diabetes
mellitus may present with characteristic
symptoms such as thirst,polyuria,
blurring of vision,and weight loss,In its
most severe forms,ketoacidosis or a non-
ketotic hyperosmolar state may develop
and lead to stupor,coma and,in absence
of effective treatment,death,
Medical Genetics
Often symptoms are not severe,
or may be absent,and consequently
hyperglycaemia sufficient to cause
pathological and functional changes
may be present for a long time
before the diagnosis is made,
Medical Genetics
The long-term effects of diabetes
mellitus include progressive development
of the specific complications of retinopathy
with potential blindness,nephropathy that
may lead to renal failure,and/or
neuropathy with risk of foot ulcers,
amputation,Charcot joints,and features
of autonomic dysfunction,including sexual
dysfunction,People with diabetes are at
increased risk of cardiovascular,peripheral
vascular and cerebrovascular disease,
Medical Genetics
Several pathogenetic processes are
involved in the development of diabetes,
These include processes which destroy the
beta cells of the pancreas with consequent
insulin deficiency,and others that result in
resistance to insulin action,The
abnormalities of carbohydrate,fat and
protein metabolism are due to deficient
action of insulin on target tissues resulting
from insensitivity or lack of insulin,
Medical Genetics
Aetiological Classification of Disorders of Glycaemia
? Type 1, (beta-cell destruction,usually leading to
absolute insulin deficiency)
– Autoimmune
– Idiopathic
? Type 2, (may range from predominantly insulin
resistance with relative insulin deficiency to a
predominantly secretory defect with or without
insulin resistance)
? Other specific types
– Genetic defects of beta-cell function
– Genetic defects in insulin action
– Diseases of the exocrine pancreas
– Endocrinopathies
– Drug- or chemical-induced
– Infections
– Uncommon forms of immune-mediated diabetes
– Other genetic syndromes sometimes associated with diabetes
? Gestational diabetes
Medical Genetics
Genetic defects
Several forms of the diabetic state may be
associated with monogenic defects in beta-cell
function,frequently characterized by onset of
mild hyperglycaemia at an early age (generally
before age 25 years),They are usually inherited
in an autosomal dominant pattern,Patients with
these forms of diabetes,formerly referred to as
maturity-onset diabetes of the young (MODY),
have impaired insulin secretion with minimal or
no defect in insulin action,
Medical Genetics
Abnormalities at several genetic
loci on different chromosomes have
now been characterized,
Medical Genetics
The most common form is
associated with mutations on
chromosome 12 in a hepatic nuclear
transcription factor referred to as
HNF1alpha,
Medical Genetics
A second form is associated
with mutations in the glucokinase
gene on chromosome 7p,
Glucokinase converts glucose to
glucose-6-phosphate,the
metabolism of which in turn
stimulates insulin secretion by the
beta cell,
Medical Genetics
Thus,glucokinase serves as the
"glucose sensor" for the beta cell,
Because of defects in the glucokinase
gene,increased levels of glucose are
necessary to elicit normal levels of
insulin secretion,
Medical Genetics
A third form is associated with
a mutation in the HNF4alpha gene on
chromosome 20q, HNF4alpha is a
transcription factor which is involved
in the regulation of the expression of
HNF1alpha,
Medical Genetics
A fourth variant has recently
been ascribed to mutations in
another transcription factor gene,
IPF-1,which in its homozygous form
leads to total pancreatic agenesis,
Medical Genetics
Specific genetic defects in other
individuals who have a similar clinical
presentation are currently being
defined,
Medical Genetics
Point mutations in
mitochondrial DNA have been found
to be associated with diabetes
mellitus and deafness, The most
common mutation occurs at position
3243 in the tRNA leucine gene,
leading to an A to G substitution,
Medical Genetics
An identical lesion occurs in the
MELAS syndrome (Mitochondrial
myopathy,Encephalopathy,Lactic
Acidosis,and Stroke-like syndrome);
however,diabetes is not part of this
syndrome,suggesting for unknown
reasons different phenotypic
expressions of this genetic lesion,
Medical Genetics
3,bronchial asthma
Bronchial asthma is the more correct
name for the common form of asthma,
The term bronchial asthma is used to
differentiate it from cardiac asthma,
Although the two types of asthma have
similar symptoms,including shortness of
breath and wheezing (a whistling sound in
the chest),they have quite different
causes,
Medical Genetics
For most people with bronchial
asthma,the pattern is periodic
attacks of wheezing alternating with
periods of quite normal breathing,
However,some people with bronchial
asthma alternate between chronic
shortness of breath and episodes of
even worse shortness of breath,
Medical Genetics
Strong risks for developing
bronchial asthma include being a
person who is genetically susceptible
to asthma and being exposed early
in life to indoor allergens,such as
dust mites and cockroaches,and
having a family history of asthma or
allergy,
Medical Genetics
Medical Genetics
Bronchial asthma attacks can be triggered
(precipitated or aggravated) by various
factors,including,
? respiratory tract infections;
? cold weather;
? exercise;
? cigarette smoke and other air pollutants;
? stress,
Medical Genetics
In sensitive individuals,asthma
symptoms can be triggered by inhaled
allergens (allergy triggers),such as pet
dander,dust mites,cockroach allergens,
molds,or pollens,Asthma symptoms can
also be triggered by respiratory infections,
exercise,cold air,tobacco smoke and
other pollutants,stress,food,or drug
allergies,
Medical Genetics
The symptoms of bronchial asthma
include,
? a feeling of tightness in the chest;
? difficulty in breathing or shortness of
breath;
? wheezing; and
? coughing (particularly at night),
Medical Genetics
Medical Genetics
Asthma is found in 3-5% of
adults and 7-10% of children,Half of
the people with asthma develop it
before age 10,and most develop it
before age 30,Asthma symptoms
can decrease over time,especially in
children,
Medical Genetics
Gene-environment interactions in
the early life origins of asthma
Medical Genetics
Genetic and Molecular Regulation of
ADAM33
ADAM33 was the first asthma
susceptibility gene identified as a result of
a genome-wide positional cloning effort,
The identification of ADAM33 as a major
risk factor involved in the pathogenesis of
bronchial hyper-responsiveness (BHR) and
airway wall remodeling provides insight
into the pathogenesis of asthma and
represents a novel therapeutic target,
Medical Genetics
The occurrence of ADAM33 in embryonic mesenchymal
cells suggests that it may be involved in airway wall
"modeling" that contributes to the early life origins of
asthma,We are conducting further studies into the genetic
and molecular regulation of ADAM33 including,
? Characterisation of the ADAM33 promoter
? Correlation of ADAM33 genotypes/haplotypes with
molecular phenotypes
? Association of ADAM33 polymorphism with early-life lung
function and COPD susceptibility
? ADAM33-environment interactions and asthma
susceptibility
