genetics lecture material Flashcards
Vitamin-D resistant rickets
X-linked dominant trait;
affects both male and female;
in males the condition is uniform in severity but in females the heterozygote is variably affected because of X-inactivation
Turner’s syndrome
aneuploidy–45XO
- female
- webbed neck
- short stature
- infertile
Klinefelter’s syndrome
aneuploidy–47XXY
- male
- tall and thin
- gynaecomastia (with cancer risk)
- infertile
- mild learning impairment
Red-green colorblindness
X-linked recessive
Duchenne muscular dystrophy
- X-linked recessive -mutation in Dystrophin gene (X-linked)
- the encoded protein normally is cytosolic and connects the cytoskeleton of muscle fibre to the ECM through the cell membrane; this provides cell stability
- in DMD there’s progressive muscle weakness, degeneration and lethality
Haemophilia
- X-linked recessive
- a rare bleeding disorder where coagulation is compromised due to deficiency in clotting factors
- haemophilia A–> lack of clotting factor VIII
- haemophilia B–> lack of clotting factor IX
(A is more common)
Rett syndrome
- X-linked dominant
- neurological disorder
-there are no affected males as the condition is early lethal; female survive due to X-inactivation
Prader willi syndrome
- affects multiple system, but primarily a neurological disorder
- caused by loss of function of genes in a particular region of chromosome 15
- some genes are only expressed on the copy that is inherited from the father (genomic imprinting)
For this syndrome:
- most cases-> a segment of paternal chromosome is deleted in each cell; missing critical genes (as, paternal=deleted; maternal=turned off)
- some others-> both copies of chromosome 15 inherited from mother (maternal uniparental disomy)
- rarely-> a mutation, translocation or other defect that inactivates the genes on paternal chromosomes
Angelman syndrome
- primarily affects nervous system
- loss of function of a gene; In certain areas of the brain, only maternal copy of this gene is active (genomic imprinting)
For this syndrome:
- most cases-> segment of maternal chromosome 15 that contains this gene is deleted
- some cases-> there’s a mutation in the maternal copy of the gene
- rarely-> both copies of chromosome 15 are from father (uniparental disomy)
Beckwith-Wiedemann syndrome
-on chromosome 11, for some genes, only the paternal inherited copy is expressed (genomic imprinting)
For this syndrome:
- (most cases)–> mutations in imprinting centres of chromosome 11 result in disrupted regulation as a result of abnormal methylation
- (some cases)–> paternal uniparental disomy results in two active copies of the paternally expressed genes and missing genes that are normally active on the maternal copy [often also accompanied by mosaicism]
(there are other causes but not needed)
in the disorder: there's either increased dosage of IGF2 (growth factor) or no expression of CDKN1C (a CDK inhibitor; i.e. a cell cycle repressor) - foetal overgrowth -multi-organ hyperplasia -increased childhood tumours
DIDMOAD
- mitochondrially inherited condition
- Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness- mitochondrial form
Kearns-Sayre syndrome
- mitochondrial inheritance
- mtDNA deletion–> multiple genes lost
- chronic progressive external ophthalmoplegia with myopathy
LHON
- mitochondrial inheritance
- mutation in NADH dehydrogenase
- leber hereditary optic neuropathy
MELAS
- mitochondrial inheritance
- tRNA (leu) mutation
- Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes
MERRF
- mitochondrial inheritance
- tRNA (lys) mutation
- Myoclonic Epilepsy associated with Ragged-Red Fibres
Pearson marrow/pancreas syndrome
- mitochondrial inheritance
- pancytopenia, lactic acidosis and exocrine pancreatic insufficiency
Down’s syndrome
-de novo mutation disease
-trisomy 21
-increased dosage of about 243 genes
-variable expressivity
–(more than 90% of times the additional copy is from mother;
this follows with the fact that in germline variants cytogenetic variants mostly arise in maternal germline)
BRCA1
-breast cancer type 1 susceptibility protein
(breast and ovarian cancer susceptibility)
- tumour suppressor gene
-the normal gene product is involved in homologous recombination mechanism of DNA repair; if HR is absent then cells rely on NHEJ, which is less accurate– therefore cells more likely to acquire mutations
-indel mutation of BRCA1 allele
( example of genetic drift– present in ashkenazi population)
-females carrying one copy of mutated allele have 80% risk of developing of developing breast/ovarian cancer by 90yrs
- it’s INCOMPLETELY penetrant
Ellis-van creveld syndrome
- Autosomal recessive
- splice site mutation
- short limb dwarfism, polydactyly etc.
- due to founder effect –common in amish population
apert syndrome
- de novo mutation disease
- missense mutation on FGFR2 (Ser-> Trp)
- prolonged signalling–> bone growth/ spermatogonial stem cell advantage (selfish positive selection)
22q11.2
-also called DiGeorge syndrome
-De novo disease
-‘q11.2’ on chromosome 22 is deleted due to NAHR
(removal of about 40 genes)
-cognitive and developmental problems; facial features(cleft palate); congenital heart defects
azospermia
- de novo mutation disease
- absence of sperms
- due to structural variants- in one of the 3 AZF regions
huntington’s disease
-autosomal dominant inheritance
-mutation is on hungtingtin gene on chr4
-number of CAG repeats are: (which codes for Glu)
<35 in normal
36-39 in maybe affected
40+ in affected
-age of onset is about 35-40yrs
polycystic kidney disease
- autosomal dominant inheritance
- can arise due to a variety of mutations in PKD1 and PKD2
- onset is 40-50 years
Albinism
- example of autosomal recessive disease
- OCA gene mutations
- as many OCA gene alleles present, trans heterozygotes are often seen (?)
Xeroderma pigmentosum
- autosomal recessive
- SNV or indel in one of the many genes encoding for components of Nucleotide excision repair machinery
phenylketonuria
-incomplete penetrance seen
- disease is associated with decreased metabolism of phenylalanine
- if recognised early, reduced phe in diet and supplements can prevent symptoms
spinal muscular atrophy
- childhood autosomal recessive neurodegenerative disease
- topic of interest for implementation of gene therapy
schizophrenia and GWAS
- SNPs on chromosome 6 tag gene C4 structural variants that are now known to underlie the association with schizophrenia
- there are 2 functionally distinct C4 genes– C4A, C4B
- higher copy number means higher expressivity and higher expressivity leads to the schizophrenia symptoms
note: C4 encodes for a protein that’s involved “component cascade” which is a pathway in innate immunity systems that eliminates pathogens; the genes in complement cascade pathway trim synapses (this may explain why there are lower synapses in schizophrenia patients)
Inflammatory bowel disease
complex disease
>200 common genetic variants are associated
suggests that problems in various biological processes could lead to IBS
McCune Albright syndrome
- caused by mosaic mutation in GNAS gene
- ONLY mosaics for GNAS gene mutation are seen in the population as mutation in all GNAS genes aren’t compatible with life
- bone, endocrine abnormalities, cafe au lait spots present
dominantly acting cancer genes
oncogenes!!!
e.g. KRAS, BRAF, MYC
recessively acting cancer genes
tumour suppressor genes!!
e.g. CDKN2A, PTEN, BRCA1
BRAF V600E
Oncogene!
(dominantly acting)
missense mutation–> is the driver mutation in >50% of malignant melanomas
-when BRAF is mutated cell cycle progression occurs without Growth factor binding to RTKs
MCL (chronic myeloid leukaemias)
-due to philadelphia chromosome- this is a mutation; a balanced structural variant (a translocation) which creates a dominantly acting fusion gene BCR-ABL1
as a result, the ABL1 activity is always on, without upstream signal
-this is an example of cancer specific to a certain tissue (as though this is a positively selected driver mutation in the context of MCL it is a neutral mutation in other cells)
Le Fraumeni syndrome
- autosomal dominant familial cancer
- inherited TP53 mutation
- somatic loss of another copy
what is a double minute? their relevance?
tiny circular DNA fragments created by unbalanced structural variants.
double minutes which encode MYC can lead to massive copy number amplifications–resulting in cancer (as Myc is an oncogene)
dominant negative mutants? relevance?
dominant negative mutations have gene products that act antagonistically to the original product.
in context of p53, (which is actually a recessively acting tumour suppressor protein), some mutations can be dominant negative
(so, mutant p53 suppresses the ability of the wild-type p53 in causing cell arrest)
Imanitib
- used for therapy for CML(chronic myeloid leukaemia) patients
- blocks BCR-AL1
vemurafenib
- used for therapy for malignant melanoma patients
- inhibits BRAF V600E
variants in which gene increase risk of colon cancer
(adenomatous polyposis coli) APC gene product
HPV (human papillomavirus)
- it’s a non-integrating virus
- it makes E6 and E7 proteins which stimulate cell to enter cell cycle; but normally the genes for E6,7 aren’t integrated into host cell
- occasionally E6 and E7 genes can be integrated into the genome–as the proteins would now be continuously expressed–predisposition to cancer!!
- HPV is only oncogenic if these genes are integrated into the genome!!
Becker-muscular dystrophy
- closely related to duchenne muscular dystrophy (both are due to abnormal dystrophin protein)
- also X linked recessive
fragile X syndrome
- X linked dominant pattern
- autistic features
- due to CGG triplet expansion on X chromosome
Kennedy disease
- rare X-linked condition
- caused by a triplet expansion (of CAG) within the sequence of androgen receptor
marfan syndrome
genetic disorder of connective tissue
hereditary nonpolyposis colorectal carcinoma
- autosomal dominant
- due to mutations in machinery of DNA mismatch repair
MODY
- autosomal dominant inheritance
- maturity onset diabetes of the young
- mutations in genes that are related to metabolism of glucose or development of tissues
HPV
E6: p53
E7: Rb
Adenovirus
E1A: Rb
E1B: p53
Simian virus
Small T: p53
Large T: Rb
MLH1
Mut1 homologoue 1
Involved in MMR
Involved in colorectal cancer
Burkitts lymphoma
-translocation between Myc and Igh
cohesinopathies
- mutation in (SMCs) cohesins and associated proteins’
- causes growth and mental retardation, limb deformities, and craniofacial abnormalities
Ataxia telangiectasia
- autosomal recessive condition
- involved with defects in detecting DNA damage
- presents in childhood with characteristic eye lesions;
- motor weakness, LD, immunodeficiency, chromosomal breaks and abnormalities [poor survival to adulthood]
BRCA2
-controls the activity of the HR protein Rad51 through direct interaction
Olaparib (lynparza)
PARP inhibitor (first) used in treatment of ovarian cancer patients with defective BRCA genes
SRC
Raus sarcoma virus
causes Sarcoma
