Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

Selig, Sara; Bruno, Sandra; Scharf, Jeremiah M.; Wang, C H; Vitale, Emilia; Gilliam, T. Conrad; Kunkel, Louis M.

doi:10.1073/pnas.92.9.3702

Cited by 48 publications

(34 citation statements)

References 33 publications

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“…Due to the facts that large scale deletions and rearrangements of the 5q13 region are specific for more severe (SMA-I) cases [5] and that we found a higher number of motoneurons undergoing abnormal migration in these cases, it is reasonable to speculate that in more severe SMA cases other genetic changes in the vicinity of SMN locus might influence the course of the disease. For example, it is not clear whether irregularly high transcription of the variable number of cadherin12 pseudogenes in the SMN region somehow relates to the pathogenesis of SMA [44].…”

Section: Discussionmentioning

confidence: 99%

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

et al. 2007

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Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy. Acta Neuropathologica, 115 (3). pp. 313-326. The role of heterotopic (migratory) motoneurons (HMN) in the pathogenesis of spinal muscular atrophy (SMA) is still controversial. We examined the occurrence and amount of HMN in spinal cord tissue from eight children with SMA (six with SMA-I and two with SMAII). All affected subjects were carrying a homozygous deletion of exon 7 in the SMN1 gene. Unlike controls, virtually free from HMN, all SMA subjects showed a significant number of HMN at all levels of the spinal cord. Heterotopic neurons were hyperchromatic, located mostly in the ventral white matter and had no axon or dendrites. More than half of the HMN were very undifferentiated, as judged from their lack of immunoreactivity for NeuN and MAP2 proteins. Small numbers of more differentiated heterotopic neurons were also found in the dorsal and lateral white matter region. As confirmed by ultrastructural analysis, in situ end labeling (ISEL) and CD68 immunoreactivity, HMN in the ventral outflow were found to have no synapses, to activate microglial cells, and to eventually die by necrosis. An unbiased quantitative analysis showed a significant negative correlation between age of SMA subjects (a reflection of the clinical severity) and the number of HMN. Subjects who died at older ages had increased number of GFAP-positive astrocytes. Complementing our previous report on motoneuron apoptosis within the ventral horns in SMA, we now propose that abnormal migration, differentiation, and lack of axonal outgrowth may induce motoneuron apoptosis predominantly during early stages, whereas a slower necrosis-like cell death of displaced motoneurons which ''escaped'' apoptosis characterizes later stages of SMA.

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Section: Discussionmentioning

confidence: 99%

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

et al. 2007

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“…L33477) (Selig et al 1995) was used as the query in a BLAST search against the dbSTS database. This sequence happens to contain a (CA) n microsatellite sequence in its 3Ј-untranslated region (3Ј UTR) that corresponds to the Généthon marker D5S411.…”

Section: Why Not Just Use Blast?mentioning

confidence: 99%

Sequence Mapping by Electronic PCR

Schuler¹

1997

Genome Res.

334

246

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The highly specific and sensitive PCR provides the basis for sequence-tagged sites (STSs), unique landmarks that have been used widely in the construction of genetic and physical maps of the human genome. Electronic PCR (e-PCR) refers to the process of recovering these unique sites in DNA sequences by searching for subsequences that closely match the PCR primers and have the correct order, orientation, and spacing that they could plausibly prime the amplification of a PCR product of the correct molecular weight. A software tool was developed to provide an efficient implementation of this search strategy and allow the sort of en masse searching that is required for modern genome analysis. Some sample searches were performed to demonstrate a number of factors that can affect the likelihood of obtaining a match. Analysis of one large sequence database record revealed the presence of several microsatellite and gene-based markers and allowed the exact base-pair distances among them to be calculated. This example provides a demonstration of how e-PCR can be used to integrate the growing body of genomic sequence data with existing maps, reveal relationships among markers that existed previously on different maps, and correlate genetic distances with physical distances.

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“…In the course of the characterization of the PMCHL genes, we established that PMCHL2 was located on chromosome band 5q13, proximal to the predisposition locus of the spinal muscular atrophy (SMA)-an autosomal recessively inherited neurodegenerative disorder with variable clinical severity (Munsat et al 1990;Viale et al 2000). Interestingly, this region of the human genome was shown to harbor a class of transcribed pseudogenes/gene-derived sequences that are similar in their organization to the PMCHL genes (Sargent et al 1994;Theodosiou et al 1994;Selig et al 1995). These sequences are not typical processed pseudogenes, but rather contain introns and exons with related copies on both the q and p arms of human chromosome 5, and show at least 90% nucleic acid sequence identity to functional genes located elsewhere in the genome.…”

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confidence: 99%

“…They were shown to be almost identical to CDH12 exons 4 and 6 and surrounding intronic sequences, respectively (Selig et al 1995). (2) Glu [5][6][7][8][9][10] , a sequence that exhibits high-sequence similarity to exons 5, 9, 10, and adjacent intronic sequences of the ␤-glucuronidase gene (GUSB), which is located on chromosome band 7q11.21 (Sargent et al 1994;Theodosiou et al 1994).…”

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confidence: 99%

Segmental Duplications in Euchromatic Regions of Human Chromosome 5: A Source of Evolutionary Instability and Transcriptional Innovation

Courseaux

Richard²,

Grosgeorge³

et al. 2003

Genome Res.

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Recent analyses of the structure of pericentromeric and subtelomeric regions have revealed that these particular regions of human chromosomes are often composed of blocks of duplicated genomic segments that have been associated with rapid evolutionary turnover among the genomes of closely related primates. In the present study, we show that euchromatic regions of human chromosome 5-5p14, 5p13, 5q13, 5q15-5q21-also display such an accumulation of segmental duplications. The structure, organization and evolution of those primate-specific sequences were studied in detail by combining in silico and comparative FISH analyses on human, chimpanzee, gorilla, orangutang, macaca, and capuchin chromosomes. Our results lend support to a two-step model of transposition duplication in the euchromatic regions, with a founder insertional event at the time of divergence between Platyrrhini and Catarrhini (25-35 million years ago) and an apparent burst of interand intrachromosomal duplications in the Hominidae lineage. Furthermore, phylogenetic analysis suggests that the chronology and, likely, molecular mechanisms, differ regarding the region of primary insertion-euchromatic versus pericentromeric regions. Lastly, we show that as their counterparts located near the heterochromatic region, the euchromatic segmental duplications have consistently reshaped their region of insertion during primate evolution, creating putative mosaic genes, and they are obvious candidates for causing ectopic rearrangements that have contributed to evolutionary/genomic instability. There is compelling evidence that gene duplication and transposition events have played essential roles during vertebrate evolution (Brosius 1999a,b;Patthy 1999;Long 2001;Friedman and Hughes 2001a;McLysaght et al. 2002). However, the importance of such evolutionary mechanisms is not restricted to ancient times. The initial sequencing and analysis of the human genome, in combination with previously published reports, have revealed that our genome is constituted of a remarkably complex pattern of both ancient and recent duplications (Lander et al. 2001;Bailey et al. 2002a). It is now estimated that ∼5% (probably more) of our genetic material is composed of duplicated genomic segments that have emerged during the past 35 million years of primate evolution. These blocks (termed segmental duplications) range in size from a few kilobases to hundreds of kilobases, and share a high degree of sequence identity (>90%). In contrast to whole-genome polyploidization events, segmental duplications have originated from the duplicative transpositions of small portions of chromosomal material, often containing intron-exon structure of known genes, and tend to be localized in pericentromeric and subtelomeric regions (for review, see In earliest studies (Viale et al. 1998(Viale et al. , 2000

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Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

Cited by 48 publications

References 33 publications

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

Sequence Mapping by Electronic PCR

Segmental Duplications in Euchromatic Regions of Human Chromosome 5: A Source of Evolutionary Instability and Transcriptional Innovation

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