Medical Genetics

多基因遗传疾病多基因遗传疾病

Polygenetic Polygenetic disordersdisorders

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Multifactorial inheritance is responsible for the greatest number of individuals that will need special care or hospitalization because of genetic diseases.

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Up to 10% of newborn children will express a multifactorial disease at some time in their life.

Atopic reactions, diabetes, hypertension, cancer, spina bifida/anencephaly, pyloric stenosis, cleft lip, cleft palate, congenital hip dysplasia, club foot, and a host of other diseases all result from multifactorial inheritance.

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The multifactorial model is

(1) Several, but not an unlimited number, loci are involved in the expression of the trait.

(2) There is no dominance or recessivity at each of these loci.

(3) The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype.

(4) The environment interacts with the genotype to produce the final phenotype.

Medical Genetics HeritabilityHeritability

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The threshold model for multifactorial traits. Below the threshold the trait is not expressed. Individuals above the threshold have the disease.

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(1) Recurrence risk increases with the number of affected children in a family.

(2) Recurrence risk increases with severity of the defect. A more severely affected parent is more likely to produce an affected child.

(3) Consanguinity slightly increases the risk for an affected child.

(4) If the two sexes have a different probability of being affected, the least likely sex, if affected, is the most likely sex to produce an affected offspring.

Risk

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1. schizophrenia , SP1. schizophrenia , SP

Schizophrenia is a humorous brain disorder characterized by delusional thinking and unique but unpopular perceptions.

Schizophrenia affects 1% of the world population.

Medical Genetics Netherlandish painter: van gogh

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German musician :Robert Alexander Schumann

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Relationship Risk

Monozygotic twins 40-50%

Dizygotic twins 17%

Children 13%

Siblings 10%

Half siblings 6%

Grandchildren 5%

Nieces, Nephews 4%

Aunts, Uncles, Cousins 2%

General Population 1%

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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

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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

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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.

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Subtypes of Schizophrenia

1. Disorganized Type 2. Catatonic Type 3. Paranoid Type 4. Undifferentiated Type 5. Residual Type ( waiting for psychiatry)

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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.

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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.

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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.

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mental health professionals generally begin advising their patients of the schizophrenic likelihood of suicide.

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Related genes——Related genes——DRD genesDRD genes DRD3 gene dopamine receptor D3, located on 3q13.3

normal function of the DRD3 gene The DRD3 gene provides instructions for

making a protein called dopamine receptor D3, which is found in the brain. This protein responds to the chemical messenger (neurotransmitter) dopamine to trigger signals within the nervous system, including signals involved in producing physical movement.

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• excitatory neurotransmitter• DRD3 expressed in endbrain 、 hippo

campi （ Emotional arousal Mental activity ）• antagonist of DRD3 receptor

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DRD2 gene (11q22.1-11.3) 141c missing DRD4 gene (11q15.5)

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5-HTR2A （ 13q14 ）• 5-HTR ： inhibitory transmitter • agonist

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• KCNN3 gene (1q21.3) K+ channel of cell membrane

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• MTHFR\RGS4\CH13L1\DISC1\ERBB4\SYN2\PMX2B\EPNR\DTNBP\NOTCH4\TRAR4\NRG1\GRIN1\BDNF\FYXD6\DAO\NOS1\G72\AKT1\CHRNA7\SLC6A4\SLC6A4\GNAL\C3\APOE\COMT\ZDHHC8\PRODH\RTN4R

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2. diabetes mellitus2. 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.

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Symptoms ： such as thirst, polyuria,

blurring of vision, and weight loss. In its most severe forms:

ketoacidosis ,state may develop and lead to stupor, coma and, in absence of effective treatment, complication ， death.

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risk ： • potential blindness• foot ulcers, features of autonomic

dysfunction, including sexual dysfunction.

• cardiovascular, peripheral vascular and cerebrovascular disease.

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Aetiological Classification of Disorders of Glycaemia

Type 1 : (beta-cell destruction, usually leading to absolute insulin deficiency)

• Type 2 : (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance)

• Gestational diabetes

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Diagnosis ： Blood sugar, urine sugarTreatment: food control (starch fructose ？ ) medicine （ Glucobay ） insulin injection

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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, have impaired insulin secretion with minimal or no defect in insulin action .

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Abnormalities at several genetic loci on different chromosomes have now been characterized.

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HNF1alpha （ hepatocyte nuclear factor ）

The most common form is associated with mutations on chromosome 12 in a hepatic nuclear transcription factor referred to as HNF1alpha .

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HNF1alpha is a key transcription factor that is essential for pancreatic beta-cell development and function

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glucokinase gene 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.

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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.

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HNF4alpha gene 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.

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IPF-1 A fourth variant has recently been

ascribed to mutations in another transcription factor gene, IPF-1, which form leads to total pancreatic agenesis . 13q12.1

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Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus.

The most common mutation occurs at position 3243 in the tRNA leucine gene, leading to an A to G substitution.

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Environmental factors:• Fat• Pregnant• Unhealthy food• Without exercise

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3. bronchial asthma3. bronchial asthma

Bronchial asthma, including shortness of breath and wheezing (a whistling sound in the chest).

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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.

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The symptoms of bronchial asthma include:

• a feeling of tightness in the chest; • difficulty in breathing or shortness of

breath; • wheezing; • coughing (particularly at night).

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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.

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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.

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• Indoor allergens, such as dust mites and cockroaches,

• Outdoor allergens such as pollen• Food such as seafood, peanut

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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.

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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.

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Gene-environment interactions in the early life origins of asthma

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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.

ADAM33, which causes the bronchiole smooth muscles to be hypersensitive.

Medical Genetics

• PHF11, comes from chromosome 13 The gene appears to regulate the blood B cells that produce Immunoglobulin E, the allergic antibody

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• TCQ2 （ 14q11.12 ） T cell receptor ， can regulate the

reaction of IGgE

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• ADRB3 Beta-adnephrin receptor ， related

with airway reactivity One such gene would be TGFB1 which

plays an important role in control of expression of antibodies.

Medical Genetics

• KCNS3• HNMT• MUC7• ILI3\ILI2B• SCGB342

……