Alu-alu recombination results in duplication of seven exons in the lysyl hydroxylase gene from a patient with the type VI variant of Ehlers-Danlos syndrome

Pousi, Birgitta; Hautala, Timo; Heikkinen, Jari; Pajunen, L.; Kivirikko, Kari I.; Myllalä, R.

doi:10.1016/0945-053x(94)90130-9

Cited by 20 publications

(27 citation statements)

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“…Enzyme Activity Assays. Lysyl hydroxylase activity was assayed by a procedure based on the hydroxylation-coupled decarboxylation of 2-oxo [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]glutarate with 0.75 mg͞ml of (Ile-Lys-Gly) 3 as the peptide substrate (19). K m values were measured as described (6,19), the pooled soluble fractions of the cell homogenate being used as the source of enzyme.…”

Section: Methodsmentioning

confidence: 99%

“…The NP-40 and glycerol buffer extracts were analyzed for lysyl hydroxylase activity with an assay based on hydroxylationcoupled decarboxylation of 2-oxo [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]glutarate with the synthetic peptide (Ile-Lys-Gly) 3 as a substrate (19). The NP-40 buffer extract, but not the glycerol extract, was found to give a high 2-oxo [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]glutarate decarboxylation rate even in noninfected cells (Table 1).…”

Section: Isolation Of Cdna Clones For Human Lysyl Hydroxylasementioning

confidence: 99%

“…Several mutations in the lysyl hydroxylase gene have recently been characterized in families with this disease (10)(11)(12)(13)(14)(15). One interesting aspect of EhlersDanlos syndrome type VI is that the deficiency in hydroxylysine shows a wide variation between tissues (1,8).…”

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confidence: 99%

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Cloning and characterization of a third human lysyl hydroxylase isoform

Passoja

Rautavuoma

Ala‐Kokko

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Lysyl hydroxylase (EC 1.14.11.4), a homodimer, catalyzes the formation of hydroxylysine in collagens. Recently, an isoenzyme termed lysyl hydroxylase 2 has been cloned from human sources [M. Valtavaara, H. Papponen, A.-M. Pirttilä, K. Hiltunen, H. Helander and R. Myllylä (1997) J. Biol. Chem. 272, 6831-6834]. We report here on the cloning of a third human lysyl hydroxylase isoenzyme, termed lysyl hydroxylase 3. The cDNA clones encode a 738 amino acid polypeptide, including a signal peptide of 24 residues. The overall amino acid sequence identity between the processed human lysyl hydroxylase 3 and 1 polypeptides is 59%, and that between the processed lysyl hydroxylase 3 and 2 polypeptides is 57%, whereas the identity to the processed Caenorhabditis elegans polypeptide is only 45%. All four recently identified critical residues at the catalytic site, two histidines, one aspartate, and one arginine, are conserved in all these polypeptides. The mRNA for lysyl hydroxylase 3 was found to be expressed in a variety of tissues, but distinct differences appear to exist in the expression patterns of the three isoenzyme mRNAs. Recombinant lysyl hydroxylase 3 expressed in insect cells by means of a baculovirus vector was found to be more soluble than lysyl hydroxylase 1 expressed in the same cell type. No differences in catalytic properties were found between the recombinant lysyl hydroxylase 3 and 1 isoenzymes. Deficiency in lysyl hydroxylase 1 activity is known to cause the type VI variant of the Ehlers-Danlos syndrome, and it is therefore possible that deficiency in lysyl hydroxylase 3 activity may lead to some other variant of this syndrome or to some other heritable connective tissue disorder.

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Section: Methodsmentioning

confidence: 99%

Section: Isolation Of Cdna Clones For Human Lysyl Hydroxylasementioning

confidence: 99%

See 1 more Smart Citation

Cloning and characterization of a third human lysyl hydroxylase isoform

Passoja

Rautavuoma

Ala‐Kokko

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…Alu insertions have been found in the vicinity of several diverse human disease-associated genes and Alu-mediated mutagenesis has been estimated to contribute to 0.4% of new human genetic diseases (Deininger and Batzer 1999). Examples include breast cancer (Miki et al 1996), acute myeloid leukemia (Strout et al 1998), neurofibromatosis (Wallace et al 1991), hemophilia B (Vidaud et al 1993), hypertension (Muratani et al 1993;Kitamura et al 1996;Anderson et al 1998), Ehlers-Danlos syndrome type VI (Pousi et al 1994(Pousi et al , 1998Toriello et al 1996;Heikkinen et al 1997), alphazero-thalassemia (Harteveld et al 1997), and Tay-Sachs disease (Myerowitz and Hogikyan 1987).…”

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confidence: 99%

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Stenger

Lobachev²,

Gordenin³

et al. 2001

Genome Res.

117

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Alu sequences, the most abundant class of large dispersed DNA repeats in human chromosomes, contribute to human genome dynamics. Recently we reported that long inverted repeats, including human Alus, can be strong initiators of genetic change in yeast. We proposed that the potential for interactions between adjacent, closely related Alus would influence their stability and this would be reflected in their distribution. We have undertaken an extensive computational analysis of all Alus (the database is at http://dir.niehs.nih.gov/ALU) to better understand their distribution and circumstances under which Alu sequences might affect genome stability. Alus separated by <650 bp were categorized according to orientation, length of regions sharing high sequence identity, distance between highly identical regions, and extent of sequence identity. Nearly 50% of all Alu pairs have long alignable regions (>275 bp), corresponding to nearly full-length Alus, regardless of orientation. There are dramatic differences in the distributions and character of Alu pairs with closely spaced, nearly identical regions. For Alu pairs that are directly repetitive, ∼30% have highly identical regions separated by <20 bp, but only when the alignments correspond to near full-size or half-size Alus. The opposite is found for the distribution of inverted repeats: Alu pairs with aligned regions separated by <20 bp are rare. Furthermore, closely spaced direct and inverted Alus differ in their truncation patterns, suggesting differences in the mechanisms of insertion. At larger distances, the direct and inverted Alu pairs have similar distributions. We propose that sequence identity, orientation, and distance are important factors determining insertion of adjacent Alus, the frequency and spectrum of Alu-associated changes in the genome, and the contribution of Alu pairs to genome instability. Based on results in model systems and the present analysis, closely spaced inverted Alu pairs with long regions of alignment are likely at-risk motifs (ARMs) for genome instability.

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“…In situ hybridization studies have shown that Alu sequences are localized predominantly to the gene-rich R (reverse) bands of metaphase chromosomes (Korenberg and Rykowski 1988), regions which are preferentially involved in homologous and nonhomologous chromosomal exchange processes (for review, see Morgan and Crossen 1977). A number of disease-associated genetic rearrangements and deletions involve Alu sequences: several Philadelphia chromosome BCR-ABL translocation breakpoints (Chen et al 1989a,b); an inversion-deletion in [3-globin (Glanzmann thrombasthemia; Li and Bray 1993); and intragenic deletions in lysyl hydroxylase (EhlersDanlos syndrome Type VI: Heikkinen et al 1994;Pousi et al 1994), low-density lipoprotein receptor (familial hypercholesteremia: Lehrman et al 1987), apolipoprotein B (hypobetalipoproteinemia: Huang et a1.1989), adenosine deaminase (ADA-SCID: Berkvens et al 1990), and complement component C1 (hereditary angioedema: Stoppa-Lyonnet et al 1990).…”

Section: Genome Research ~ 1043mentioning

confidence: 99%

Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.

Smith¹,

Lee²,

Szabo³

et al. 1996

Genome Res.

252

189

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Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCAI. Loss of the wild-type allele in >90% of tumors from patients with inherited BRCAI mutations indicates tumor suppressive function. The low incidence of somatic mutations suggests that BRCAI inactivation in sporadic tumors occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117,143-bp DNA sequence encompassing BRCA1 was obtained by random sequencing of four cosmids identified from a human chromosome 17 specific library. The 24 exons of BRCAI span an 81-kb region that has an unusually high density of AJu repetitive DNA {41.5%), but relatively low density [4.8%) of other repetitive sequences. BRCAI intron lengths range in size from 403 bp to 9.2 kb and contain the intragenic microsatellite markers DI7S1323, DI7SI322, and DI7S855, which localize to introns 12, 19, and 20, respectively. In addition to BRCAI, the contig contains two complete genes: RhoT, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles. Partial sequences of the IAI-JB B-box protein pseudogene and lip JS, an interferon induced leucine zipper protein, reside within the contig. An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13. The order of genes on the chromosome is: centromere-lFP JS-VATI-P, hoT-BRCAI-IAI-JB-telomere.[The sequence data described in this paper have been submitted to GenBank under accession no. L78833.] Inherited mutations in the breast-ovarian cancer susceptibility gene, BRCA1 (Hall et al. 1990;Miki et al. 1994), confer a lifetime risk of breast cancer greater than 80% and an increased risk of ovarian cancer (Newman et al. 1988;Easton et al. 1993;Ford et al. 1994). Evidence for tumor suppressive function of BRCA1 derives from the high proportion (87%) of truncating germ-line mutations, which likely represent loss-of-function alterations (Castilla et

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Alu-alu recombination results in duplication of seven exons in the lysyl hydroxylase gene from a patient with the type VI variant of Ehlers-Danlos syndrome

Cited by 20 publications

References 0 publications

Cloning and characterization of a third human lysyl hydroxylase isoform

Cloning and characterization of a third human lysyl hydroxylase isoform

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.

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