A homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers–Danlos syndrome type VI

Hyland, James; Ala‐Kokko, Leena; Royce, Peter M.; Steinmann, Beat; Kivirikko, Kari I.; Myllylä, Raili

doi:10.1038/ng1192-228

Cited by 95 publications

(57 citation statements)

References 18 publications

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“…Furthermore, mutations in PITX2 have also been associated with significantly reduced central corneal thickness in humans and mice [Asai-Coakwell et al, 2006]. Mutations in PLOD1 cause Ehlers-Danlos syndrome type VI (MIM# 130050), a connective tissue disorder characterized by joint hypermobility, skin fragility, and hypotonia with ocular manifestations including microcornea, retinal detachment, and fragility of the globe [Hyland et al, 1992;Yeowell and Walker, 2000]. We have shown that PITX2A and FOXC1 are each capable of independently activating transcription from the PLOD1 and FOXO1 promoters in vitro.…”

Section: Discussionmentioning

confidence: 99%

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

et al. 2011

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Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with AxenfeldRieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR

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Section: Discussionmentioning

confidence: 99%

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

et al. 2011

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“…Hyl also serves as acceptor for the attachment of collagenspecific glycans (Schegg et al 2009). Defects of lysyl hydroxylation lead to diseases such as Ehlers-Danlos type-VI (Hyland et al 1992), Bruck syndrome (van der Slot et al 2003), and skeletal dysplasia (Salo et al 2008), demonstrating the biological importance of this post-translational modification.…”

Section: Introductionmentioning

confidence: 99%

Recombinant expression of hydroxylated human collagen in Escherichia coli

Rutschmann

Baumann

Cabalzar

et al. 2013

Appl Microbiol Biotechnol

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Collagen is the most abundant protein in the human body and thereby a structural protein of considerable biotechnological interest. The complex maturation process of collagen, including essential post-translational modifications such as prolyl and lysyl hydroxylation, has precluded large-scale production of recombinant collagen featuring the biophysical properties of endogenous collagen. The characterization of new prolyl and lysyl hydroxylase genes encoded by the giant virus mimivirus reveals a method for production of hydroxylated collagen. The coexpression of a human collagen type III construct together with mimivirus prolyl and lysyl hydroxylases in Escherichia coli yielded up to 90 mg of hydroxylated collagen per liter culture. The respective levels of prolyl and lysyl hydroxylation reaching 25 % and 26 % were similar to the hydroxylation levels of native human collagen type III. The distribution of hydroxyproline and hydroxylysine along recombinant collagen was also similar to that of native collagen as determined by mass spectrometric analysis of tryptic peptides. The triple helix signature of recombinant hydroxylated collagen was confirmed by circular dichroism, which also showed that hydroxylation increased the thermal stability of the recombinant collagen construct. Recombinant hydroxylated collagen produced in E. coli supported the growth of human umbilical endothelial cells, underlining the biocompatibility of the recombinant protein as extracellular matrix. The high yield of recombinant protein expression and the extensive level of prolyl and lysyl hydroxylation achieved indicate that recombinant hydroxylated collagen can be produced at large scale for biomaterials engineering in the context of biomedical applications.

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“…Furthermore, the residual activity of EDSVI cells preferentially directed toward type IV collagen (28) suggests the presence of isoforms for lysyl hydroxylase. The presence of isoforms may also explain our previous observations that cells from an EDSVI patient producing a truncated form of lysyl hydroxylase 1, which lacks the highly conserved carboxyl-terminal portion of the molecule, nevertheless have detectable lysyl hydroxylase activity (13).…”

Section: Lysyl Hydroxylase Isoform (2) 6833mentioning

confidence: 53%

“…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).…”

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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 homozygous stop codon in the lysyl hydroxylase gene in two siblings with Ehlers–Danlos syndrome type VI

Cited by 95 publications

References 18 publications

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

Recombinant expression of hydroxylated human collagen in Escherichia coli

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

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