Abnormal protein truncation

Abnormal protein truncation due to the presence of premature stop codons (PTCs) is the cause of genetic diseases such as cystic fibrosis and Duchenne muscular dystrophy. 

Genetic disorders of HDL metabolism have also resulted in greater understanding of the molecular regulation of HDL metabolism. Nonsense or missense mutations in apoA-I can result in substantially reduced HDL-C levels due to rapid catabolism of structurally abnormal or truncated apoA-I proteins. Tangier disease is a rare autosomal codominant disorder characterized by markedly low HDL-C and apoA-I levels and caused... 

The answer is C. Production of a truncated protein indicates that a mutation has occurred, but this phenomenon may have arisen from a frameshift mutation (insertion or deletion) or by a nonsense mutation. The most likely possibility is a nonsense mutation because sequence analysis of the truncated protein showed that it had normal (wild-type) sequence. Insertion and deletion events often produce a stretch of garbled or abnormal protein sequence at the C-terminal end of the truncated protein arising from out-of-frame translation of the mRNA downstream of the mutation until a stop codon is encountered. 

Small-scale mutations include point mutations, which are single nucleotide substitutions, and small deletion and insertion mutations. Point mutations can be further classified into (1) missense mutations, which lead to amino acid change and result in production of abnormal protein, (2) silent mutations, which do not lead to a change in amino acid, and (3) nonsense mutations, in which substitution of a single nucleotide results in formation of a stop codon and a truncated protein. Deletion and insertion mutations result in deletion or insertion of a number of nucleotides that is divisible by 3. This leads to a change in the number of amino acids and a shorter or longer protein, or to an insertion or deletion of a number of nucleotides that is not divisible by 3. This... 

Brill J, Klocke R, Paul D, Boison D, Gouder N, Klugbauer N, Hofmann F, Becker CM, Becker K (2004) entla, a novel epileptic and ataxic Cacna2d2 mutant of the mouse. J Biol Chem 279 7322—7330. Brodbeck J, Davies A, Courtney JM, Meir A, Balaguero N, Canti C, Moss FJ, Page KM, Pratt WS, Hunt SP, Barclay J, Rees M, Dolphin AC (2002) The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function. J Biol Chem 277 7684—7693. 

As previously described, one of the major neuropathological hallmarks of AD are NFTs. NFTs are composed of paired helical filaments, with the principal protein subunit of paired helical filaments being abnormally hyper-phosphorylated tau (p-tau). Physiologically, tau protein is located in the neuronal axons and in the cytoskeleton. There are six different tau isoforms. Total tau (t-tau) and truncated forms of monomeric and phosphorylated tau are released and can be found in the CSF [71, 80]. 

Nonsense mutation A mutation that creates an abnormal stop codon and thus causes translation to terminate prematurely the resulting truncated protein is usually nonfunctional. 

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