Genetics Flashcards
1
Q
What are chromosomes?
A
- are structures found within the cell nucleus
- composed of
- DNA
- RNA
- polysaccharides
- histone
- non histone proteins
-
thin thread like structures that have a
- short p arm
- long q arm
- separated by a centromere
- only seen under light microscope during cell division when condensed x1000 magnifcation
2
Q
How many chromsomes does the normal human have?
A
- karotype of normal human is 46 chromosomes= diploid number
- this includes 22 autosomal pairs and **2 sex **chomosomes
3
Q
What are the chromsomes basic shape?
A
- All depend on centromere location
-
Metacentric
- chromosomes have p and q arms of approx **equal length **
- e.g. chromosome 1
-
Submetacentric
- Chromosomes have a p and q arms of different length
- e.g. chromosome 6
-
Acrocentric
- centromere is near one end
- so very short p and q long
- e.g chromosome 13
4
Q
What is DNA?
A
- Polymer of deoxyribonucleotides
- composed of
-
nitrogenous base
- purine or pyridamine
- contain genetic information
- a sugar
- phosphate group
-
nitrogenous base
5
Q
What are the purine bases?
A
- Adenine
- Guanine
6
Q
What are the pyrimidine bases?
A
- Thymine
- Cytosine
7
Q
What is the structure of DNA?
A
- Watson and Crick deduced the Double helical structure of DNA with paired bases at the centre
- Hydrogen bonds between the bases hold them together
- Adenine always paired w Thyamine = ‘AT’
- Guanine always paired with Cytosine = “GC”
8
Q
What process allow somatic cells to grow and divide?
A
- Mitosis
- replication of DNA involves unwinding of DNA
- allowing a complementary DNA daughter strand to be formed using the original strand as a template
- semi conserative process as each new helix contains one of the original chromosomal strands
9
Q
What do genes code for?
A
- Protein synthesis
10
Q
What happens in transcription?
A
- Templates are produced from the DNA in the form of messenger ribonucleic acid ( mRNA)
- the mRNA exits nucleus into the cellular cytoplasm
- By combining with other RNA moelcules such as tRNA ( transfer RNA) and ribosomal RNA ( rRNA) protein synthesis takes place at the ribosomes
11
Q
What is the role of proteins?
A
- Mechanical tissue strength seen in skeletal tissue due to collagen
- muscle contraction occurs with interaction of actin and myosin protein filaments
- proteins act as transport molecules and enzymes during biological reactions
- immune system in the form of antibodies
12
Q
What is the process of meisosis?
A
- in sexual reproduction the chromosomes separate to form a haploid number, including one copy of each autosome and a single sex chromosome
- a child inherits one half of his or her autosomal pair and one sex chromosome from each parent
13
Q
Name some whole chromosome abnormalities?
A
- Monosomy = Turner’s syndrome
- Trisomy= Down’s syndrome/ Kleinefelter
14
Q
What is the name given to loss or gain of whole chromosomes?
A
- Aneuploidy
- can effect autosomes or sex chromosomes
15
Q
What is Turner’s syndrome?
A
-
Loss of one X chromosome
- ie XO ( paternal X chromsome absent- sporadic event)
- incidence 1 in 2000 live births
- exclusively females
- short female
- skeletal abnormalities
- cubitus valgus
- medial tibial exostosis
- short 4th MC/ MT
- cranoifacial
- renal tract
- cardiovascular anomalies
16
Q
What is trisomy ?
A
- Cells have an extra chromosome
17
Q
What is down’s syndrome?
A
- Trisomy 21 ( extrachromosome 21)
- Incidence 1 in 660 live births
- Risk assoc with increase maternal age > 35 yrs
- 95% aetiology is failure of separation of the autosomal pair during meisosis
- 3.5 % due to translocation of one autosomes
- 2.5 % due to mosaicism (where some cells have 47 chromosomes)
- orthopaedic manifestations
- atlantoaxial instability
- joint laxity with recurrent dislocation of patella
- increased risk of SUFE
18
Q
What is Kleinfelter’s syndrome?
A
- An addition of an extra X chromsome
- so XXY
- incidence is 1 in 1000 male births
- Tall , thin male with infertility and hypogonadism
19
Q
What is the genotype ?
A
- The inherited genetic code that produces the **physical appearance= ** phenotype
20
Q
What is an allele?
A
- One or two alternative forms of the gene that can have the same locus on the homologous chromosome and are responsible for alternative traits
- if alleles similar = homozygous trait
- if alleles different = heterpzygous trait
21
Q
Describe how the structure abnormalites of chromosomes can occur?
A
-
Point mutations
- specific nucleotide bases
-
Deletions
- loss of part of chromosome
-
Inversions
- inversion of chromosome by 180 degrees-> misreading of genetic code
-
Translocations
- movement of genetic material from one chromosome to naother
22
Q
What is penetrance?
A
- relates to the probability that the phenotype will be expressed
23
Q
What is incomplete penetrance?
A
- defined as inheritance of the mutant gene without expression of the phenotype of the disorder
24
Q
What is variable expressivity?
A
- In which a patient always expresses some of the symptoms of the mutant gene
25
What is autosomal dominant inheritance?
* Affected individuals are **heterozygous for the mutation**
* homozygous individuals often don't survive
* **50% of inheritance** from one heterozygous parent
* M= F affected
26
Name some examples of autosomal dominant inheritance?
* Achondroplasia
* Osteogenesis imperfecta
* Neurofibromatosis type 1
* Marfan's syndrome
* multiple epiphyseal dysplasia
* mutliple hereditary exostoses
27
What is achondroplasia?
* Most common form of disporportionate rhizomelic dwarfism ( short limb)
* inherited as complete penetrance
* **87%** result of **new mutation**
* gene encoding on chromosome 4, p16.3
* mutation affects **Fibroblast growth factor receptor 3 ( FGFR3)**
28
What is Osteogenesis imperfecta?
* A generalised disease of connective tissue due to a quantitative or qualitative defect of **type 1 collagen**
* **Sillence classified**
* **1-IV**
* with subgroups in 1 and IV of **A /B**
* where B = **dentinogenesis imperfecta**
* **Autosomal dominant condition- cases from unaffected parents is _mosaicism_**
* **pro-alpha 1 chain is encoded by COL1A1 gene on chromosome 17 and the pro-alpha 2 chain is encoded by COL1A2 gene on chromosome 7**
29
What is neurofibromatosis inherited as?
* Autosomal dominance
* Complete penetrance but high variable expressivity
* 50% of pts have a fresh gene mutation
* gene encoded on chromosome 17 locus q11.2
* the gene encodes the protein **Neurofibromin** which acts as a tumour suppressor
30
What is the defect in marfan's syndrome?
* Mutation in fibrillin 1 gene
* connective tissue disorder
* arachnodactyly
* scoliosis (50%)
* protrusio acetabuli (15-25%)
* ligamentous laxity
* recurrent dislocations (patella, shoulder, fingers)
* pes planovalgus
nonorthopaedic conditions
* cardiac abnormalities
* aortic root dilatation
* possible aortic dissection in future
* mitral valve prolapse
* superior lens dislocations (60%)
* pectus excavatum
* spontaneous pneumonthoraces
* dural ectasia (\>60%)
* meningocele
31
What is the genetic mutation in mutliple hereditary exostoses?
* **EXT 1 and EXt2 gene**
* autosomal dominant
* individuals with the EXT1 mutation have a more severe presentation compared to patients with the EXT2 mutation including
* higher rate of chondrosarcoma 5-10% of transformation, proximal lesions more likely to undergo transformation than distal ones
* more exostoses
* more limb malalignment with less forearm and knee range of motion
* more pelvic and flatbone involvement
32
What is autosomal recessive inheritance?
* **Affected** individuals are **homozygous** for the genetic mutation
* **Heterozgyous** individuals are **carriers**
* 25% of producing an affected individual from 2 parent carriers
* M= F affected
* autosomal recessive conditions often produce errors of metabolism due to deficiency of specific enzymes
33
Can you name some examples of autosomal recessive conditions?
* **Mucopolysaccharidoses** ( except Hunters)
* **Sickle cell anaemia**
* **Diastrophic dysplasia**
34
What is type 1 mucopolysaccharidosis?
* **Hurler syndrome**
* mental retardation
* disporportinate dwarfism
* diaphyseal bordening of short misshapen boness
* flaring of rib cage
* widening medial end of clavicle
* anterior wedging of verterbral bodies-\> kyphosis/ thoracolumbar gibbus
* odontoid hypoplasia
* **cloudy cornea**
* caused by **alpha 1 iduronidase deficiency**
* **Dermatan sulphate in urine**
* **death in first decade of life**
35
What is type IV mucopolysaccharidosis?
* **Morquio**
* **Type A= deficiency in galactosamine 6 sulphatase**
* chromosome 16 q24.3
* **Type B= deficiency in beta -galactosidases**
* chromosome 3 p21.33
* **Proportinate dwarfism**
* _Normal mental IQ_
* _both need enzyme to break down glycoaminoglycans- esp keratan sulphate interferes with cartilage at growth plate_
* **Keratan sulphate in urine**
* **type A more severe**
* **both live into adulthood**
* skeletal
* **platyspondyly**
* **ovoid vertebra & odontoid hypoplasia**
* **flaring of rib cage**
* **flattening of femoral heads**
* **Genu valgum**
* **Joint laxity**
36
What other form of mucoploysaccharidosis is inherited by autosomal recessive?
**San filipio**
* Multiple enzyme defiencies
* Proportinate dwarfism
* Mental retardation
* **clear cornea**
* Urine- **Heparan sulphate in urine**
* **death in 2nd decade of life**
37
What is the inhertance of sickle cell disease?
* Autosomal recessive of single gene leading to the subsitution of **glutamine for valine** at position **6** of the **beta-globulin chain of haemaglobin**
38
What is the genetic defect in disatrophic dysplasia?
* Sulphate transporter
* DTDST gene (SLC26A2) on chromosome 5
* failure of formation of the secondary centres of ossification ( epiphysis)
* rhizomeliz dwarfism
* hitcher's thumb
* cauliflower ears
* autosomal recessive
39
What is the genetic defect in multiple epiphyseal dysplasia?
* **Cartilage oligomeric matrix protein (COMP)** or **type IX collagen** ( **COL9A2) **
* causes type 2 collagen dysfunction as type IX collagen acts as a link protein for type 2 collagen
* **autosomal dominant**
* **A form of dwarfism ( short limbed) characterized by irregular, delayed ossification at multiple epiphyses**
40
What is x linked dominant inheritance?
* Either sex affected
* phenotype is dominant when a heterozygous female expresses the phenotype
* 50% sons and 50% daughters risk inheritance from an affected mother
41
Name an example of x linked dominant inheritance?
* **Hypophosphataemic rickets**
* males express disease fully but females have expressivity in the heterozygous genotype
* PEX ( cellular endopeptidases)
42
What is X linked recessive inheritance?
* **Phenotype is recessive** when expressed by a **homozygous female**
* **All males are affected**
* **Heterozygous females are carriers**
* 25% of producing a normal male/female
* an affected male transmits the affected gene thru all his daughters
43
Name some x linked recessive disorders?
* **Duchenne muscular dystrophy**
* deficiency of protein **dystrophin **
* **Haemophilia A**
* deficiency in **clotting factor VIII**
* **Hunter's syndrome - mucopolysaccharidosis**
* **sulpho-iduronate-sulphatase deficiency**
* **-\> accumulation of dermatan and sulphate in urine**
* **proportionate dwardfism**
* **mental retardation**
* **clear cornea**
44
What is the genetic mutation in spondyloepiphyseal dysplasia?
* caused by abnormal synthesis of **Type II collagen**
* **A form of short-trunk dwarfism caused by a defect in the secondary ossification center (epiphysis) **
* **mutation = COL2A1 on chromosome 12 **
* inheritance
```
* **autosomal dominant (SED congenita)
X linked recessive (SED tarda)
random mutation (50% of cases)**
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