A Large Duplication in the Gene for Lysyl Hydroxylase Accounts for the Type VI Variant of Ehlers-Danlos Syndrome in Two Siblings

Hautala, Timo; Heikkinen, Jari; Kivirikko, Kari I.; Myllylä, Raili

doi:10.1006/geno.1993.1074

Cited by 66 publications

(34 citation statements)

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“…The mutation is adjacent to a cysteine residue at position 680 and is six amino acids upstream of an asparagine-linked oligosaccharide attachment site. The other two conservative base changes of C318 --T and C1230 T do not produce codon changes and have been previously reported (12,18).…”

Section: Resultssupporting

confidence: 66%

A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene.

Marshall²,

Elsas³

et al. 1994

J. Clin. Invest.

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In the present study, we have isolated and sequenced the complementary DNAs of two mutant alleles for lysyl hydroxylase (LH) in fibroblasts from one patient (AT750) with EhlersDanlos syndrome type VI (EDS VI). We have identified a putative mutation in each allele which may be responsible for the patient's decreased LH (normalized to prolyl hydroxylase) activity (24% of normal). Intermediate levels of LH activity were measured in the patient's parents, who are clinically normal (father 52%; mother 86%). After the cloning of cDNAs and amplification by PCR, sequence analysis revealed two equally distributed populations of cDNAs for LH in the AT750 cell line. Each allele revealed different but significant changes from the normal sequence. In one allele (allele 1), the most striking change was a triple base deletion that would result in the loss of residue Glu532. The most significant difference in the other allele (allele 2) was a G -A change which would produce a Gly678 -> Arg codon change in a highly conserved region of the enzyme. Restriction analysis identified that allele 1 was inherited from the proband's mother and allele 2 from the father. This study represents the first example of compound heterozygosity for the LH gene in an EDS VI patient, and it appears that there is an additive effect of each mutant allele on clinical expression in this patient. (J. Clin. Invest. 1994.

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Section: Resultssupporting

confidence: 66%

A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene.

Marshall²,

Elsas³

et al. 1994

J. Clin. Invest.

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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%

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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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“…The complete cDNA-derived amino acid sequence has been reported for the enzyme from chick (9), human (10,11), and rat (12). The enzyme has also been characterized at the genomic level (7), and the first mutations in the lysyl hydroxylase gene have been characterized in patients with type VI of the Ehlers-Danlos syndrome (EDSVI) 1 (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Cloning and Characterization of a Novel Human Lysyl Hydroxylase Isoform Highly Expressed in Pancreas and Muscle

Valtavaara

Papponen

Pirttilä

et al. 1997

Journal of Biological Chemistry

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118

104

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We report the isolation and characterization of cDNA clones for a novel isoform of lysyl hydroxylase (lysyl hydroxylase 2), a posttranslational enzyme of collagen biosynthesis. The open reading frame predicted a protein of 737 amino acids, including an amino-terminal signal peptide. The amino acid sequence has overall similarity of over 75% to the lysyl hydroxylase (lysyl hydroxylase 1) characterized earlier. This similarity is even higher in the carboxyl-terminal end of the molecules. Lysyl hydroxylase 2 contains nine cysteine residues, which are conserved in lysyl hydroxylase 1. Furthermore, the conserved histidines and aspartate residues required for lysyl hydroxylase activity are present in the sequence. Northern analysis identified a transcript of 4.2 kilobases, which was highly expressed in pancreas and muscle tissues. Expression of cDNA in insect cells using a baculovirus vector yielded proteins with lysyl hydroxylase activity and an antiserum against a synthetic peptide of the deduced amino acid sequence recognized proteins with molecular weights of 88 and 97 kDa in homogenates of the transfected cells.

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A Large Duplication in the Gene for Lysyl Hydroxylase Accounts for the Type VI Variant of Ehlers-Danlos Syndrome in Two Siblings

Cited by 66 publications

References 0 publications

A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene.

A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene.

Cloning and characterization of a third human lysyl hydroxylase isoform

Cloning and Characterization of a Novel Human Lysyl Hydroxylase Isoform Highly Expressed in Pancreas and Muscle

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