6-Octapeptide repeat insertion

Krasemann S, Zerr I, Weber T, Poser S, Kretzschmar H, Hunsmann G, Bodemer W (1995) Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene. Brain Res Mol Brain Res 34 173-176... 

Insertions encoding additional integral copies of an octapeptide repeat present in a tandem array of five copies in the normal protein (Fig. 48-1). 

Occasionally patients with a clinical phenotype typical of sCJD have other octapeptide repeat mutations, but the exact significance of these mutations in this group is unclear in many [12]. Those involving one, two or three additional repeats may be coincidental findings, as these have been found in healthy control populations [13]. Several patients with 4-OPRI insertions have been reported associated with a late-onset, short duration clinical course, often with an absence of family history and so are often mistaken for sCJD one possible explanation for this observation is discussed below. 

Fig. 7. Plot versus the amino acid sequence of the relative intensities, Irei, of the steady-state i N H -NOEs of the backbone amide groups of bPrP(23-230). In the box from positions 51 to 91 the pattern of NOE values is indicated for the octapeptide insertion between the positions 67 and 68 (Fig. 1), where the open rectangle indicates that only one value was measured for two overlapped Gly residues. The circles indicate that identical patterns prevail for the other octapeptide repeats (see text). The regular secondary structures of the globular domain are indicated at the bottom, and the first residue with a positive NOE-value, Vail22, is identified.

The octapeptide repeat region is not required for the conversion of Prpc pj.pSc propagation of the disease process. Nevertheless, extra-repeat insertional mutations in one PRNP allele trigger disease. It is conceivable that disorder of copper binding in these extended protein species might feature in the formation of altered PrP isoforms and/or PrP aggregation. In this regard, it is noteworthy that PrP is... 

Fig. 2. Sequence content of spa repeats at nucleotide and amino acid levels. Repeats differing at the nucleotide level may be identical at the amino acid level. Identical codons are depicted using the same colors equivalent codons corresponding to synonymous mutations are colored with similar hues. The translated sequence reveals a conserved octapeptide motif comprised almost exclusively of charged amino acids and is suggestive of a surface-exposed loop region with repeating turns. Repeats Tl-Zl bear a single codon insertion between positions 1 and 2 most common spa types begin with one of these repeats, such that the initial repeat is usually 27-bp in length (vs. 24-bp).

---