Phenotypic variability Flashcards
How do gene/environmental interactions contribute towards phenotypic variance?
Contribute to the progression and outcome of the disease for each patient.
Affects prognosis
What is multiple endocrine neoplasia type 1 (MEN1)?
Increased chance of developing adenomas within endocrine tissue.
Which genes are mutated within MEN1?
Mutation within tumor suppressor gene (synthesizes menin).
What is the inheritance pattern for MEN1?
Autosomal dominant inherited conditions
How do environmental triggers affect the phenotypic expression of MEN1?
Promotes tumour formations, tumours associated with parathyroid gland, pancreatic islet & anterior pituitary.
Which protein is mutated within hereditary hemochromatosis?
HFE
Which receptor is bound to transferrin, enabling iron entry into hepatocytes?
Transferrin receptor I
Which hormone regulates iron release within enterocytes?
Hepcidin
What is the pathophysiology of hereditary hemochromatosis?
HFE protein regulates iron levels within hepatocytes by preventing transferrin from binding to transferrin receptor I. HFE mutation reduces iron transportation into the live, therefore hepcidin synthesis is reduced. This causes increase ferroportin release of iron from enterocytes, resulting in iron overload.
What percentage of patients with hereditary hemochromatosis have clinically relevant iron accumulation?
10%
Why are women more likely to be protected from hereditary hemochromatosis?
Menstrual bleeding
What are genetic modifiers?
Life-course of disease and symptoms present are modified by presence of other genes. These gens can either improve or worsen the condition.
Name three cystic fibrosis genetic modifiers
delf5f08, TFB1 gene, FCGR2A
How does the delf5f08 gene alter the phenotypic expression of CF?
Homozygotes of the gene mutation classified with severe/mild lung disease
How does the TGFB-1 gene alter the phenotype of CF?
Encodes for transforming growth factor beta-1, variants associated with severe lung disease phenotype. Increases lung inflammation.
Which gene increases the risk of developing respiratory tract infections with patients of CF?
Immunoglobulin Fc-gamma receptor II (FCGR2A)
Variant increases chance of developing chronic pseudomonas aeruginosa infection by 4 fold
Which is VHL?
Von-Hippel Lindau syndrome
Dominant inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms. Retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors
Which gene modifier alters the phenotype of VHL?
Cyclin D1 (CCND1) G allele increases number of retinal angiomas compared with AA homozygotes. G allele associated with earlier diagnosis of CNS hemangioblastoma by 2 fold.
What is the function performed by the cyclin d1 receptor?
Cyclin d1 regulator of cell cycle progression, overexpression leads to the development of cancer
Which protein is involved in muscular dystrophy?
Dystrophin
Which are the two main muscular dystrophy conditions?
Becker muscular dystrophy
Duchenne muscular dystrophy
When is the age of onset of Becker muscular dystrophy?
12 years old, loss of ambulation varies from adolescence onwards
When does death usually occur with patients expressing BMD?
Death in the fourth/fifth decade
When is the age of onset for DMD?
4.6 years
When do patients with DMD become wheelchair dependent?
10 years
What percentage of patients with DMD develop cardiac failure?
15% of patients, with a median age of 21.5 years
When is the median death for patients with DMD?
17 years
Which type of gene mutation is associated with muscular dystrophy disorders?
Deletions
How does a gene mutation cause DMD?
A deletion within the dystrophin gene causes a frameshift deletion, thus this means no active dystrophin is produced (triplet of a sequence of bases altered, altering codon sequence)
Presence of premature stop codon
How does BMD mutation occur?
Deletion causes stop codon, therefore a truncated functional dystrophin protein is produced
What are unstable gene mutations?
Diseases termed trinucleotide repeat disorders, the underlying cause of the disease is trinucleotide repeat expansion. Mutation whereby a region of three repeated nucleotides within the genome increases in frequency during DNA replication.
Below which number of repeats conforms for gene stability and protein functionality?
27 repeats
What is DNA slippage?
Increased repeat frequency exceeds the stability threshold, whereby mutation loses stability during DNA replication and the number of repeats increases during subsequent rounds of DNA replication – Increase trinucleotide repeats, changing protein function
What is the relationship between repeat frequency and phenotypic severity?
Greater number of repeats results in increased severity of phenotype. Characterized by an earlier onset of disease, greater severity of symptoms in each succeeding generation as the number of repeats increases.
Which trinucleotide sequence is associated with Huntington’s disease?
CAG
What causes Huntington’s disease?
Caused by the expansion of the region of the huntingtin gene (Cytosin, adenine, guanine), monogenetic (affecting only one gene), a neurodegenerative disorder
What is the inheritance pattern for Huntington’s disease?
Autosomal dominance
Which amino acid is encoded by CAG?
Glutamate
What is formed from multiple glutamate polypeptide sequences?
Poly Q tract (Polyglutamine)
Fewer than ___ CAG repeats is considered stable?
27
Between which CAG repeat range forms an intermediate phenotype?
27-35 repeats
What number of CAG repeats forms the characteristic phenotype?
36-39 (Not all carries affected by disease)
What number of CAG repeats affects all carriers?
40+
