Huntington Disease Phenocopy Is a Familial Prion Disease

Abstract

Huntington disease (HD) is a common autosomal dominant neurodegenerative disease with early adult-onset motor abnormalities and dementia. Many studies of HD show that huntingtin (CAG)n repeat-expansion length is a sensitive and specific marker for HD. However, there are a significant number of examples of HD in the absence of a huntingtin (CAG)n expansion, suggesting that mutations in other genes can provoke HD-like disorders. The identification of genes responsible for these "phenocopies" may greatly improve the reliability of genetic screens for HD and may provide further insight into neurodegenerative disease. We have examined an HD phenocopy pedigree with linkage to chromosome 20p12 for mutations in the prion protein (PrP) gene (PRNP). This reveals that affected individuals are heterozygous for a 192-nucleotide (nt) insertion within the PrP coding region, which encodes an expanded PrP with eight extra octapeptide repeats. This reveals that this HD phenocopy is, in fact, a familial prion disease and that PrP repeat-expansion mutations can provoke an HD "genocopy." PrP repeat expansions are well characterized and provoke early-onset, slowly progressive atypical prion diseases with an autosomal dominant pattern of inheritance and a remarkable range of clinical features, many of which overlap with those of HD. This observation raises the possibility that an unknown number of HD phenocopies are, in fact, familial prion diseases and argues that clinicians should consider screening for PrP mutations in individuals with HD-like diseases in which the characteristic HD (CAG)n repeat expansions are absent.

Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotype

“…The insertion of octapeptides in the coding region of the PRNP gene has been reported in only one family (Moore et al 2001;Xiang et al 1998) and, as in the current report, other studies did not find this type of mutation in the PRNP gene (Bauer et al 2004;Stevanin et al 2003), which suggests that this must be a very rare genetic cause of disease in HDL patients. Nevertheless, the possible existence of HDL-causative point mutations in the PRNP gene in our sample remains open.…”

“…However, some patients with Huntington disease-like (HDL) presentations do not carry any expansion of the (CAG) n tract in the HD gene. Sequence alterations in two loci responsible for a HDL phenotype (PRNP and JPH3) have already been identified: for PRNP (HDL1), a 192-nucleotide insertion within the prion protein gene (PRNP), localised in chromosome 20p (Xiang et al 1998), that gives rise to an expanded prion protein with eight extra octapeptide repeats (Moore et al 2001); for JPH3 (HDL2), a CAG/CTG repeat in the junctophilin-3 gene (JPH3) , localised in chromosome 16q23-24 (Kambouris et al 2000;Nishi et al 2000). Other possible causative genes remain unknown, although a gene associated with an autosomal recessive transmission of HDL phenotype has been mapped to chromosome 4p15.3 (Kambouris et al 2000), and some evidence suggests that CAG repeat expansions in unidentified genes could also be responsible for a similar clinical presentation .…”

Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation

“…9 The fourth family was a 3 generation Swedish kindred in which 4 of 7 affected subjects had chorea, initially attributed to Huntington's disease (HD). Following the exclusion of HD in this kindred 10 and after identifying the PRNP gene mutation 11 …”

Context dependent neuroprotective properties of prion protein (PrP)

“…Some cases of diagnosed HD are actually caused by a mutation in the gene encoding PrP (PRNP) rather than any alteration to the huntingtin gene. 44,45 PRNP mutations can also be associated with some PD-like symptoms and neuropathology 46 and some demonstrate similarities to the tauopathies. 47 Collinge and colleagues described a kindred segregating pre-senile dementia, AD, HD, PD, Pick's disease, as well as prion disease (GerstmannStraussler-Scheinker syndrome and CJD).…”