A Huntington Disease–Like Neurodegenerative Disorder Maps to Chromosome 20p

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor disturbance, cognitive loss, and psychiatric manifestations. The disease is associated with a CAG trinucleotide-repeat expansion in the Huntington gene (IT15) on chromosome 4p16.3. One family with a history of HD was referred to us initially for predictive testing using linkage analysis. However, the chromosome 4p region was completely excluded by polymorphic markers, and later no CAG-repeat expansion in the HD gene was detected. To map the disease trait segregating in this family, whole-genome screening with highly polymorphic dinucleotide-, trinucleotide-, and tetranucleotide-repeat DNA markers was performed. A positive LOD score of 3.01 was obtained for the marker D20S482 on chromosome 20p, by two-point LOD-score analysis with the MLINK program. Haplotype analysis indicated that the gene responsible for the disease is likely located in a 2.7-cM region between the markers D20S193 and D20S895. Candidate genes from the mapping region were screened for mutations.

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

“…[10][11][12] The neuropathological features of IPD with 8-OPRI include varying degrees of spongiosis, cell loss, and astrocytosis in different areas of the brain, 7,9,10 and the presence of prion protein (PrP) plaques in the cerebellum. 8,13,14 Brain homogenates from one subject in each of the Che and M-E families were injected into monkeys.…”

“…10 His mother was also affected by HDL1. The subject was adopted at the age of 3 and was in normal health until the age of 29.…”

“…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 …”