Therefore, codon 129 plays a twofold role in determining the phenotypic heterogeneity of the D178N mutation: On the mutant allele it determines the phenotype (either FFI or CJD 178) of the two diseases associated with the D178N mutation, and on the normal allele it specifies disease duration (or severity) and some additional features of each of the two diseases.
Furthermore, homozygous and heterozygous FFI patients differ slightly in clinical and pathological features. It has been observed that FFI has on average a shorter duration in homozygous (M/M) patients than in heterozygous (M/V) patients. Furthermore, since the other normal allele may have either the M or the V codon at position 129, patients may also be either M/M (homozygous) or M/V (heterozygous) at codon 129 when both alleles are considered. It was determined that all patients with FFI have codon M at position 129 of the mutated allele (one copy of the gene inherited from one of the two parents), whereas all patients with CJD 178 have codon V in that position. It was instead shown that although the pathogenic mutation is identical, FFI and CJD 178 differ genetically at codon 129 of the PrP gene that in humans is the site of a common methionine/valine (M/V) polymorphism (i.e., in normal individuals codon 129 may specify either the M or the V amino acid in position 129 of the PrP).
The association of two phenotypically distinct diseases with the same mutation, known as phenotypic heterogeneity, was commonly believed to result from the modification of the disease phenotype by environmental factors, another gene, or the paternal or maternal origin of the mutation.
However, the D178N mutation is also associated with a familial disease that is quite different in clinical and pathological features from FFI and is identified as Creutzfeldt–Jakob disease with mutation at codon 178 (CJD 178) because it has a phenotype similar to that of the most common form of sporadic human prion disease ( Fig. Fatal familial insomnia is invariably associated with a mutation at codon (the unit of the gene that specifies one amino acid) 178 of the PrP gene leading to the substitution of the amino acid aspartic acid with asparagine and identified as D178N.
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