Genetic Basis of DM Flashcards
What is DM?
A chronic disease that occurs when blood glucose is higher than usual.
A group of metabolic diseases that affect the body’s ability to use the energy found in food
What are the classifications of diabetic syndromes?
Monogenic & Polygenic
Monogenic: Noeonatal DM, MODY
Polygenic: Type 1 and Type 2
What are the monogenic defects of beta cell function? (4)
- MODY: 14 types associated with different genes
- Mt DNA 3243 maternally-inherited diabetes and deafness
- Wolfram syndrome
- Wolcott-Rallison syndrome
What are monogenic defects in insulin action?
- Insulin receptor Type A insulin resistance
- ISNR Laprechaunism
- ISNR Rabson-Mendehnhall syndrome
- PPARG familial partial lipodystrophy
What are other genetic syndromes sometimes associated with DM?
- Down syndrome
- Friedreich’s ataxia
- Myotonic dystrophy
- Prader-Willi Syndrome
- Turner syndrome
What is type 1 DM?
A chronic autoimmune disorder caused by destruction of insulin secreting cells –> hyperglyceia
What is the peak onset age of T1D?
Around puberty age, but it can occur at any age
What is the evidence relating T1D to genetic disorders?
Identical twins are more likely to both have T1D than non-identical twins
Where is the major susceptibility gene of T1DM located?
Mainly in the HLA region
What is insulin-dependent DM and its relation to it with T1D?
About 18 regions of the genome have been linked with influencing T1D risk
What has HLA been designated as in terms of Insulin-dependen DM?
Designated as IDDM1 and insulin gene INS IDDM2
What is HLA Class II region (IDDM1) contribution to T1D?
Encodes the major susceptibility genes to Type 1 DM
What is IDDM2 contribution to T1D?
VNTR upstream of the insulin gene
What is IDDM12’s contribution to T1D?
Associated with T1D as well as other autoimmune diseases
What is PTPN22 gene’s contribution to T1D?
Negative T-cell activation and development
What is the major genetic factor of T1D?
MHC complex on chromosome 6p21 with over 200 known genes, many of which are involved in immune function
What are the two major subclasses of MHC complex?
Class I and class II genes which correspond to HLA
Which genes are most strongly associated with T1D?
HLA-DR
HLA-DQ
HLA-DP
How is predisposition to T1D better determined?
By haplotypes:
DRB1-DQB1 haplotypes
What is the best single genetic marker for T1D?
DQB1 gene
What can certain mutations of the insulin gene lead to?
Hyperinsulinemia
What kind of mutations on the insulin gene can lead to hyperinsulinemia?
- Missense mutations lead to defective receptor binding and hyperinsulinemia
- Some mutations affecting the conversion of proinsulin to insulin cause hyperinsulinemia
Where is the insulin gene located?
Chromosome 11p15, and it has been designated as IDDM2
What is the function of insulin?
Regulates metabolism and is the key that unlocks the cell’s glucose channel
What are the three classes that are located upstream of the insulin gene and are strongly associated with T1DM?
Class 1: associated with lower mRNA in the thymus, low thymic insulin-hampered negative selection
Class 2: 80 repeats
Class 3: appears to generate higher levels of insulin mRNA in the thymus –> increased efficiency of delteion of insulin reactive T-cell clones during development of immune system
What are CTLA-4 known as?
IDDM12
Where are CTLA-4 located?
On chromosome 2q33
What is the fucntion of CTLA-4?
Encodes a cell receptor that plays a role in T cell apoptosis –> negatively regulated T-cell function
What have CTLA-4 varients been associated with?
T1D as well as other autoimmune diseases: A49G polymorphism
What is the function of PTPN22?
Encode lymphoid-specific tyrosine phosphatase
Plays an important role in the autoimmune response
PTPN22 variants regulate insulin autoimmunity and progression to T1D
Where is PTPN22 located?
On the p arm of chromosome 1
What is PTPN22?
An inhibitor of T cell activation –> negatively regulates T-cell function
Can T1D be prevented?
It cannot be prevented
What is the relation between genetics and prevention of T1D?
A clear pattern of inheritance is lacking, but genetic predisposition might explain up to 50% of the risk
What is T2D?
A group of genetically heterogenous metabolic disorders that cause glucose intolerance
What is the pathogenesis of T2D?
Insulin levels increase in the blood
Cells become resistant to insulin
Blood glucose and insulin levels are high
Fatty acid levels are also high
The pancreas decreases insulin production
Blood glucose remains high
Type 2 diabetes
What are the chances that individuals with a positive family history of T2D devlop it themselves?
2 to 6 times more likely than those who do not have a history of diabetes in their family
What is the relation between he genetic component and T2D?
Strong genetic component
Why has it been difficult to find genes for T2D>
Late age onset
Polygenic inheritance
Multifactorial inheritance
What does polygenic refer to?
Caused by multiple genes that may interact with
What does multifactorial refer to?
Caused by genetic and environmental risk factors
Where is transcription factor 7 - like 2 found?
Chromosome 10q25
What is the function of transcription factor 7-like 2?
- Regulates pancreatic islet cell function, such as proliferation and cell survival
- Downregulation of insulin secretion
What is the relation between TCF2L2 and T2D?
People with type 2 DM are more likely to carry a genetic variant of this gene
Where is fat-mass and obesity-associated (FTO) gene located?
Chromosome 16q12
What is the function of FTO gene?
- Modulates the gene expression and governs energy balance
What is the FTO gene usually associated with?
The strong association between the FO gene and the incidence of obesity
FTO SNPs significantly correlated with the BMI
Where is the peroxisome proliferator-activated receptor γ located?
Chromosome 3p25
What is the peroxisome proliferator-activated receptor γ?
The target of hypoglycemic drugs
May be responsible for about 25% of T2D cases
Where are ABCC8 and KCNJ11 located?
Chromosome 11p15.1
What are ABCC8 and KCNJ11?
Both genes that are ATP-sensitive potassium channels
What is the function of ABCC8 and KCNJ11?
play a key role in regulating the release of hormone such as insulin and glucagon in the beta cells of pancreas
What do mutations in either ABCC8 or KCNJ11 lead to?
Mutations in either gene can affect the potassium channel activity and insulin secretion –> leading to the development of T2D
Is T2D preventable?
It is preventable: maintaining age-appropriate body weight and exercising
What is monogenic diabetes?
Encompasses relatively rare forms of non-autoimmune diabetes caused by single-gene defects
What is the age of diagnosis for a monogenic form of diabetes?
Age a diagnosis can vary from birth to later in life:
–> Neonatal/infantile
–> Adolescent and young adults
What is the mode of inheritance of the monogenic form of diabetes?
If inherited it can be:
–> AD
–> AR
–> X - linked
What types of mutations could lead to the monogenic form of diabetes?
Inherited mutations and sporadic/de novo
Which kind of mutation is usual in neonatal diabetes?
Sporadic/de novo
What are the two main forms of neonatal DM?
- Transient neonatal DM
- Permanent neonatl DM
What is transient NDM?
TNDM sets in before six months of age, but usually before the first birthday, the child recovers, and the debates seem to go away
What is permanent neonatal DM?
Diabetes again sets usually before 6 months of age, but unlike TNDM, the diabetes continues even beyond the first birthday and is usually lifelong
What is KCJN11?
Potassium channels that regulated insulin secretion
What kind of mutations can lead to severe NDM?
Activating mutations of KCJN11 cause a severe form of NDM
What are the dominantly acting mutations of NDM?
KCJN11
ABCC8
INS
HFN1B
Which mutations are recessively acting?
GCK
PTF1A
EIF2AK3
IPF1
Some INS and ABCC8
What mutation leads to X-linked NDM?
FOXP3
What is the definition of MODY?
A heterogeneous disorder due to heterozygous monogenic mutations in one of at least 14 different genes
What % of T2D cases does MODY account for?
5%
What kind of defect leads to MODY?
Single gene defects (monogenic diabetes affecting beta cells)
–> Autosomal dominant inheritance
–> Multiple generations affected
What is the onset of MODY?
Early age at onset (< age 25 years)
What is the relation between MODY and familial genetics?
Runs strongly in families, onset in at least 1 family member < 25years of age
What is MODY characterized by?
Absence of obesity, no ketosis, and no evidence of beta cell autoimmunity
–> Hyperglycemia often corrected by diet
What is MODY often misdiagnosed as?
T1D or T2D
What is the gene name of MODY 1?
HNF4A
What is the locus of MODY1?
20q13
What is the gene function of MODY 1?
Transcription factor
What is the primary defect of MODY 1?
Pancreas
What is the % MODYof MODY 1?
About 5%
What is the gene name of MODY 2?
GCK
What is the locus of MODY 2?
7p13
What is the gene function of MODY 2?
Hexokinase IV
What is the primary defect of MODY 2?
Pancreas/liver
What is % MODY of MODY 2?
About 15%
What is the gene name of MODY 3?
HNF1A
What is the locus of MODY3?
12q24
What is the primary defect of MODY 3?
Pancreas/kidney
What is the % MODY of MODY 3?
About 65%
What is the function of MODY1?
Controls genes involved in glucose, cholesterol, and fatty acid metabolism. Controls transcription of HNF1A (MODY3)
What is the function of MODY 2?
Required for glucose metabolism and insulin secretion; acts as a glucose sensor
What is the function of MODY 3?
Regulates the expression of insulin and other genes involved in glucose transport/metabolism. Influences expression of HNF4A (MODY1)
How MODY 1 inherited?
AD mutations in the HNF4a gene
Where is the hepatocyte nuclear factor 4-a expressed?
In the liver, kidney, intestine, and pancreatic islet cells
What is the role of HNF4A in the pancreas?
Required for glucose metabolism and expression and secretion of normal insulin gene
What is the role of HNF4A in the liver?
Required for hepatic gluconeogenesis
What is MODY 2?
AD inherited disease caused by inactivating mutation in GCK gene
What is GCK?
A glucose sensor expressed in pancreatic beta cells
What are the functions of the GCK?
- Encodes the glucokinase enzyme
- A key enzyme in glucose metabolism that catalyzes the conversion of glucose to glucose-6-phosphate and controls glucose-mediated insulin secretion
- A key player in glucose hemeostasis maintainance
Which one is the only MODY gene that is not a TF expressed in beta cells and the liver?
MODY 2
What are patients with MODY usually like?
Usually asymptomatic:
1. Characterized by mild non-insulin-dependent fasting hyperglycemia
How are the majority of MODY 2 cases diagnosed?
Routine examinations during preganncy or school-based urine glucose tests
What is MODY3?
Inherited AD disease due to a loss of function mutation in the HNF1A gene
What is the function of the HNF1A gene?
- Regulates the expression of insulin and other genes involved in glucose transport and metabolism
- Involved in ATP production and insulin secretion by maintaining glucose flux
What is the most common cause of MODY 3?
Mutation in the TCF1
What is the result of HNF1a mutations?
- Decrease GLUT 2 and glucose uptake
- Severe insulin secretory defect
- May contribute to abnormal islet cell development
What is the onset of each MODY?
MODY 1: severe
MODY 2: mild
MODY 3: Severe
What is the frequency of complications for each MODY subtype?
MODY 1: Frequent
MODY 2: Rare
MODY 3: Frequent
How can you differentiate between Type 2 DM and MODY? (5)
Age: T2DM –> older
MODY –> child/young
Pathophysiology:
T2DM: beta cell dysfunction AND insulin resistance, whilst MODY is only beta cell dysfunction
Role of environment is considerable in T2DM but minimal in MODY
Obesity is frequent is T2DM but rare in MODY
Inheritance of T2DM is polygenic or heterogenic, but MODY is AD
What are the benefits of genetic testing for diabetes?
A positive result for any form of monogenic diabetes makes it easier to correctly diagnose and accurately predict the risk of diabetes in relatives
Less invasive and more effective treatment
