CAG Repeat Expansion in Autosomal Dominant Familial Spastic Paraparesis: Novel Expansion in a Subset of Patients

Abstract

Autosomal dominant familial spastic paraplegia (FSP) is a genetically heterogeneous neurodegenerative disorder displaying anticipation for which three loci have been mapped to the chromosomal positions 14q11.2-q24.3 (SPG3), 2p21-p24 (SPG4) and 15q11.1 (SPG6). The repeat expansion detection (RED) method has been used to demonstrate expanded CAG repeats in some FSP families that map to SPG4. We analyzed 20 FSP families, including four for which there is evidence for linkage to SPG4, and found that in most cases the repeat expansion detected by RED is due to non-pathogenic expansions of the chromosome 18q21.1 SEF2-1 or 17q21.3 ERDA1 locus. Polymorphic expansions at SEF2-1 and ERDA1 appear frequent and may confound RED studies in the search for genes causing disorders demonstrating anticipation. In six FSP families, however, CAG repeat expansion was detected in a subset of affected and at-risk individuals that did not result from expansion of the SEF2-1 and ERDA1 loci. Overall, 11 of 37 (30%) of the FSP patients with a CAG/CTG repeat expansion are unaccounted for by the SEF2-1 and ERDA1 loci, compared with two of 23 (9%) of the unaffected at-risk individuals and none of 19 controls. In the majority of cases these novel expansions were shorter than those previously reported.

A Fine Integrated Map of the SPG4 Locus Excludes an Expanded CAG Repeat in Chromosome 2p-Linked Autosomal Dominant Spastic Paraplegia

“…Recently, Benson et al (1998) analyzed 20 AD-HSP families with the RED method, including 4 kindreds showing linkage to the SPG4 locus, and demonstrated that most repeat expansions detected by this technique were caused by nonpathogenic expansions of the chromosome 18q21.1 SEF2-1 (Breschel et al, 1997) and 17q21.3 ERDA1 (Nakamoto et al, 1997) loci. However, a novel CAG repeat expansion was suggested to be the cause of the disease in 6 of the 20 families studied (Benson et al, 1998).…”

The hereditary spastic paraplegias

“…Anticipation (increasing disease severity or decreasing age at onset in subsequent generations) is a feature of such diseases, and reflects the fact that the CAG repeat expansion may increase in size from generation to generation [56]. Anticipation has been described for SPG4-and SPG3-linked ADPHSP families, and recent molecular genetic data suggest that CAG repeat expansions are implicated in SPG4-linked ADPHSP [24,43,[53][54][55][59][60][61]. However, a conclusive answer as to whether trinucleotide repeat expansions are involved is likely to require cloning of the responsible genes.…”

Allelic distribution of CTG18.1 in Caucasian populations: association studies in bipolar disorder, schizophrenia, and ataxia

“…Previous studies using the RED technique are difficult to interpret since CTG18.1 and ERDA1 account for a large portion of the RED products. 10,19,21 There is some evidence for the involvement of ERDA1 in bipolar disorder. Verheyen et al 19 reported a significantly larger proportion of bipolar patients carrying one or two ERDA1 alleles Ͼ40 repeats with a negative correlation between age of onset and CAG/CTG length in the offspring of eight BP pedigrees.…”