X-Linked Cutis Laxa

Ph, Byers; Rc, Siegel; Ka, Holbrook; As, Narayanan; Börnstein, Paul; Hall, Judith G.

doi:10.1056/nejm198007103030201

Cited by 188 publications

(27 citation statements)

References 27 publications

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“…The disorder in mice, inherited in an X-linked recessive fashion, is due to marked decrease in lysyl oxidase activity in the relevant connective tissues (34,35). Although it has been proposed that lysyl oxidase deficiency could result in the clinical features of the Marfan syndrome, lysyl oxidase deficiency in humans is an X-linked disorder with the clinical features ofcutis laxa, accompanied by internal organ and bony involvement (36). Furthermore, direct assay of lysyl oxidase activity in our patient and in cultured fibroblasts from other patients with the Marfan syndrome (37) have shown it to be normal.…”

Section: Discussionmentioning

confidence: 58%

Marfan syndrome: abnormal alpha 2 chain in type I collagen.

Byers¹,

Siegel²,

Peterson³

et al. 1981

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

101

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Cells in culture from a woman with a variety of the Marfan syndrome produce two species ofthe a2 chains of type I collagen. One a2 chain appears normal; the abnormal chain has a higher apparent molecular weight than normal and migrates more slowly during electrophoresis in sodium dodecyl sulfate/ polyacrylamide gels. A similar change in electrophoretic behavior is seen in the preproa2 chain and the pNa2 chain (which contains the amino-terminal extension). Asymmetric cleavage of the pepsin-treated procollagens with a fibroblast collagenase locates the abnormal segment amino terminal to the cleavage site, and analysis of cyanogen bromide peptides of collagenase cleavage peptides and of whole collagens indicates that the abnormal segment is in either the a2CB3 peptide or the short segment of c2CB5 amino terminal to the collagenase site ofthe altered a2 chain. The higher apparent molecular weight is consistent with the insertion of a small peptide fragment of approximately 20 amino acids. This alteration in chain size has marked effects on crosslinking because collagen from the patient's skin was 5-10 times more extractable in nondenaturing solvents than that from control skins. Although the abnormal chain was not found in several other individuals with the Marfan syndrome, these findings suggest that the phenotype may be the expression ofa variety ofprimary structure alterations in the chains of type I collagen that interfere with normal crosslink formation.The Marfan syndrome (1-4) is a group of inherited connective tissue disorders that share certain clinical features: severe cardiovascular abnormalities (valvular heart disease and aortic dissection), skeletal alterations (arachnodactyly, pectus deformities, and kyphoscoliosis), and ocular lens dislocation. Despite considerable clinical interest (1) and research activity (3, 4), a clear understanding of the syndrome at the biochemical level has not emerged. Investigations ofglycosaminoglycan synthesis (5-7) and of collagen metabolism (8-13) have suggested that alterations in these macromolecules may be important in the pathogenesis of the syndrome. Dermal fibroblasts from some patients with the Marfan syndrome have been shown to have an increased rate of synthesis ofhyaluronic acid (5, 6), and cellfree systems from these cells also synthesize hyaluronic acid at a higher than normal rate (7). It is not clear, however, that this is the primary disorder rather than a secondary change. Similarly, it is not clear that increased extractability ofcollagen from tissues or of that synthesized by cultured cells reflects the primary biochemical disturbance.Recently Siegel and Chang (11) MATERIALS AND METHODS Clinical Summary. The patient, a 39-year-old woman, was the only affected child of three in the family; both parents were unaffected. She was noted to have equinovarus deformities of both feet at birth; arachnodactyly was first noted at age 9; lumbar scoliosis became apparent and a heart murmur was heard at age 10. Because ofpain and progressive deformity, the...

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Section: Discussionmentioning

confidence: 58%

Marfan syndrome: abnormal alpha 2 chain in type I collagen.

Byers¹,

Siegel²,

Peterson³

et al. 1981

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

101

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“…Dysregulation of the LOX-family of proteins is strongly associated with heritable connective tissue and fibrotic disorders (44–46), cardiovascular diseases (47,48), and cancers. In cancers, the LOX-family of proteins is thought to play multiple roles in processes important to cancer progression, namely cell growth, adhesion, motility, and invasion (49,50).…”

Section: Loxl2 In Diseasementioning

confidence: 99%

Human lysyl oxidase-like 2

Moon

Finney

Ronnebaum

et al. 2014

Bioorganic Chemistry

118

108

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Lysyl oxidase like-2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises Cu(2+)- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. LOXL2 is proposed to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 has also been proposed to regulate extracellular and intracellular cell signaling pathways. Dysregulation of LOXL2 has been linked to many diseases, including cancer, pro-oncogenic angiogenesis, fibrosis and heart diseases. In this review, we will give an overview of the current understandings and hypotheses regarding the molecular functions of LOXL2.

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“…Loss of function mutations in ATP7A, a copper transporter localized to the Golgi apparatus, cause Menkes disease or a milder disease, occipital horn syndrome (OHS) (Das et al, 1995). OHS, also known as X-linked CL displays LOX deficiency associated with impaired crosslinking of elastin and collagen (Byers et al, 1980). Recessive mutations in the gene for the A2 subunit of the vacuolar proton pump, ATP6V0A2, cause ARCL2A (Kornak et al, 2008).…”

Section: CL and The Secretory Pathwaymentioning

confidence: 99%

Cutis laxa: Intersection of elastic fiber biogenesis, TGFβ signaling, the secretory pathway and metabolism

Urban

Davis

2014

Matrix Biology

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Cutis laxa (CL), a disease characterized by redundant and inelastic skin, displays extensive locus heterogeneity. Together with geroderma osteodysplasticum and arterial tortuosity syndrome, which show phenotypic overlap with CL, eleven CL-related genes have been identified to date, which encode proteins within 3 groups. Elastin, fibulin-4, fibulin-5 and and latent transforming growth factor-beta-binding protein 4 are secreted proteins which form elastic fibers and are involved in the sequestration and subsequent activation of transforming growth factor-beta (TGFβ). Proteins within the second group, localized to the secretory pathway, perform transport and membrane trafficking functions necessary for the modification and secretion of elastic fiber components. Key proteins include a subunit of the vacuolar-type proton pump, which ensures the efficient secretion of tropoelastin, the precursor or elastin. A copper transporter is required for the activity of lysyl oxidases, which crosslink collagen and elastin. A Rab6-interacting goglin recruits kinesin motors to Golgi-vesicles facilitating the transport from the Golgi to the plasma membrane. The Rab and Ras interactor 2 regulates the activity of Rab5, a small guanosine triphosphatase essential for the endocytosis of various cell surface receptors, including integrins. Proteins of the third group related to CL perform metabolic functions within the mitochondria, inhibiting the accumulation of reactive oxygen species. Two of these proteins catalyze subsequent steps in the conversion of glutamate to proline. The third transports dehydroascorbate into mitochondria. Recent studies on CL-related proteins highlight the intricate connections among membrane trafficking, metabolism, extracellular matrix assembly, and TGFβ signaling.

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X-Linked Cutis Laxa

Cited by 188 publications

References 27 publications

Marfan syndrome: abnormal alpha 2 chain in type I collagen.

Marfan syndrome: abnormal alpha 2 chain in type I collagen.

Human lysyl oxidase-like 2

Cutis laxa: Intersection of elastic fiber biogenesis, TGFβ signaling, the secretory pathway and metabolism

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