Quality Assessment of Whole Genome Mapping Data in the Refined Familial Spastic Paraplegia Interval on Chromosome 14q

Abstract

Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Three loci on chromosome 14q (SPG3), 2p (SPG4), and 15q (SPG6) were shown to be responsible for AD-FSP. Analysis of recombination events in three SPG3-linked families allowed us to narrow the critical interval from 9 to 5 cM. An ∼5-Mb YAC contig comprising 32 clones and 90 STSs was built from D14S301 to D14S991, encompassing this region of 14q21. Fifty-six ESTs assigned previously to this region with radiation hybrid (RH) panels Genebridge 4 and G3 were precisely localized on the YAC contig. The 90 STSs positioned on the contig were tested on the TNG RH panel to compare our YAC-based map with an RH map at a high level of resolution. Comparison between our map and the whole genome mapping data on this interval of chromosome 14q is discussed.

A New Locus for Autosomal Dominant “Pure” Hereditary Spastic Paraplegia Mapping to Chromosome 12q13, and Evidence for Further Genetic Heterogeneity

“…Our results confirm the presence of extensive genetic heterogeneity in ADPHSP. Previously, four loci for ADPHSP had been identified, on chromosomes 2p, 8q, 14q, and 15q, and had been narrowed to regions of 3 cM, 3.4 cM, 5 cM, and 7 cM, respectively (in a family with complicated HSP, the phenotype mapped to a 0-cM interval at the SPG4 locus, but it is possible that the responsible gene in this family may be different from that involved in autosomal dominant pure HSP [Heinzlef et al 1998]) (Hazan et al 1993(Hazan et al , 1994Hentati et al 1994b;Fink et al 1995;Bü rger et al 1996;Scott et al 1997;Paternotte et al 1998;Hedera et al 1999;Reid et al, in press-a). We have now identified a fifth locus for ADPHSP, in a 9.2-cM region between D12S368 and D12S83, at chromosome 12q13 (Genome Database).…”

The hereditary spastic paraplegias

“…Mean age at 998 onset in SPG4-, SPG6-and SPG8-linked families is similar and relatively late, in the 3rd or 4th decade [15,24,33,48,49,52]. On the other hand, SPG3-linked families have an early mean age at onset of under 10 years [47,50,51,53,57]. Finally, a group of families in the United Kingdom for which linkage at all known ADPHSP loci was excluded had a significantly younger age at onset than a group of SPG4-linked families and an SPG8-linked family in the United Kingdom [15,49].…”

“…Interestingly, Table 5 Genetic loci for ADPHSP There are four known loci, exclusion of linkage at all of these loci in three United Kingdom families giving strong evidence of a fifth. The chromosome 8q locus has been mapped only recently, in two families, and therefore the proportion of ADPHSP families linked to this locus is not yet known [15,24,31,33,[46][47][48][49][50][51][52][53][54][55][56][57] Gene the same L1-CAM mutation may result in either an Xlinked hydrocephalus phenotype or a MASA phenotype [66]. L1-CAM is a cell-surface glycoprotein which is expressed on the axons of postmitotic neurones and which is involved in neuronal migration and neurite extension [67].…”

Clinical and genetic study of a large Italian family linked to SPG12 locus

“…HSP has been divided into two forms: pure and complicated. [4][5][6][7][8][9][10][11][12][13] Two causative genes, spastin and atlastin, have been identified for the SPG4 and SPG3A loci, which account for approximately 42% and 9% of ADHSP families studied. 1 The upper limbs are not involved.…”