Question

Mutant alleles can cause a dominant pedigree inheritance pattern in various ways. Discuss the following examples. Your discussion should include enough molecular detail to prove you understand how each example fits the category.

1) 3pts - Shh [sonic hedgehog] gain of function - Polydactyl

2) 3pts - loss of heterozygosity – retinoblastoma - Rb

3) 3pts - dominant negative – p53

4) 3pts - haploinsufficiency – hypercholesterolemia.

Answer 1

Answer:

1)  Shh [sonic hedgehog] gain of function - Polydactyly

The SHH gene is responsible for giving instructions for making a protein called Sonic Hedgehog. This protein act as a chemical signal that is important for developmentof an embryo. It plays a role in cell growth, cell specialization, and the normal shaping (patterning) of the body. This protein is important for development of the brain and spinal cord (central nervous system), eyes, limbs, and many other parts of the body.

Polydactyly : It is a condition in which a person is born with extra fingers or toes. This condition have several types and tends to run in families due to genetic mutations or environment causes. The most common treament will be surgical removal.

this congenital periaxial condition is caused by ectopic expression of the signalling molecule Sonic Hedgehog (SHH) in the developing limb bud.The gene responsible for this condition is GLI3 and they are DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling.  it is responsible for preaxial polydactyly type IV (PPD-IV) -  extra digits next to the thumb or big toe (hallux) .

2) loss of heterozygosity – retinoblastoma (Rb) - results in loss of the whole gene and the surrounding chromosomal region.

Retinoblastoma (RB) tumors arise when both alleles of the RB1 gene are inactivated by two mutational events (M1 and M2). M1 can be an initial germline or somatic mutation; M2 is frequently loss of heterozygosity (LOH), which makes the cell homozygous or hemizygous for the original mutation. LOH is the major mechanism by which many cancers are initiated. Proximal and distal flanking markers on chromosome 13 were informative in 13 tumors, allowing evaluation of the mechanisms by which LOH occurred. Mitotic recombination was implicated in 6 (46%) of the 13 tumors.

3) dominant negative – p53

p53 is a tumor suppressor gene and mutation of this gene is the most common genetic alteration in human cancer. This mutant p53 can have a dominant negative effect over wild-type p53 or it can gain of function activity independently of the wild-type protein.The chromatin immunoprecipitation is performed to determine the ability of wild-type p53 to bind to its endogenous target genes in the presence of various p53 mutants. This p53 missense mutants markedly reduce the binding of wild-type p53 to the p53 responsive element in the target genes of p21, MDM2, and PIG3. mutant p53 exerts its dominant negative activity by abrogating the DNA binding, and subsequently the growth suppression, functions of wild-type p53.

4)haploinsufficiency – hypercholesterolemia.

haploinsufficiency - it is a situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally. also known as a condition that arises when the normal phenotype requires the protein product of both alleles, and reduction of 50% of gene function results in an abnormal phenotype, can be due to a number of problems, One of the two copies of the gene may be missing due to a deletion. A mutation in the gene may have wiped out production of message. Or the message or the protein produced by the cell may be unstable or degraded by the cell.

Many mutated genes can cause high blood cholesterol levels, with consequent early atherosclerosis and coronary events. The most common errors involves the low‐density lipoprotein receptor (LDLR) gene, haploinsufficiency of which leads to slow clearance of LDL‐cholesterol and homozygous mutation of which leads to extreme hypercholesterolaemia and coronary disease during childhood. Familial defective apolipoprotein B (FDB) involving APOB transmits as an autosomal dominant trait with incomplete penetrance and affects ApoB, the ligand within LDL particles for the receptor. PCSK9 also transmits as an autosomal dominant trait, with high penetrance. PCSK9, proprotein convertase subtilisin kexin type‐9, is secreted and by binding to the LDL receptor promotes receptor degradation, gain‐of‐function mutations increasing binding and reducing receptor availability. LDLRAP1, a clathrin adaptor protein, if defective on both alleles, causes autosomal recessive hypercholesterolaemia in which there is failure to internalise the receptor.

hope it helps!