Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied several members of a family with an X-linked form of cutis laxa; the affected males have mild skin laxity, a characteristic facies, skeletal abnormalities, structural abnormalities of the genitourinary tract, and low serum copper levels. The activity of lysyl oxidase, a copper-dependent enzyme involved in cross-link formation in collagen, was decreased in skin-biopsy specimens (13 to 26 per cent of normal) and in culture medium from cells to two affected males (15 to 20 per cent of normal). Immunoreactive lysyl oxidase from skin of both patients was virtually undetectable by immunodiffusion assay. The amounts of lysyl-derived aldehydes (the product formed in collagen and elastin by lysyl oxidase) and of cross-links formed from these products were decreased in dermal fibroblasts in culture. Collagen extractability from these cells was increased in culture. These findings suggest that lysyl oxidase deficiency provides the biochemical basis of the X-linked form of cutis laxa.
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PMID:X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity. 610 92

Skin biopsies from thirteen patients suffering from Ehlers-Danlos syndrome, including 6 of the mitis type, 4 of the benign hypermobile type, one of the X-linked type, one of the ocular type and one of the periodontitis type, were studied by electron microscopy after routine preparation. Collagen fibrils showed a distorted arrangement of bent, curled or twisted fibrils and thread-like material. Similar changes may be seen in the skin of other hereditary disorders of connective tissue. However, abnormal collagen fibrils in normal skin suggests one of eight types of Ehlers-Danlos syndrome. Clinical variants cannot be differentiated on the basis of ultrastructural findings. Elastic fibres were normal without degenerative changes. Perineurium was lacking in dermal nerves of most patients. Fibroblast-like cells showed no cystic cisterna of endoplasmic reticula.
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PMID:Dermal changes in Ehlers-Danlos syndrome. 673 46

Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations of the WAS protein (WASP) gene. All hematopoietic stem cell-derived lineages, including platelets, express WASP. Platelets from WAS patients are smaller than their normal counterparts and defects in platelet aggregation and actin polymerization have been reported. To determine if WASP is important for normal platelet function, we examined its role in signal transduction. We found that collagen but not thrombopoietin or thrombin induces a rapid and robust increase in tyrosine phosphorylation of platelet-associated WASP. Collagen-induced tyrosine phosphorylation of WASP was inhibited by cytochalasin D and wortmannin, respectively, suggesting that actin polymerization and phosphatidylinositol 3-kinase (PI3-kinase) play a role in the induction of tyrosine phosphorylation of WASP. Binding of glutathion S-transferase (GST)-Grb2 to WASP was seen in the lysate of resting platelets. The binding was reduced when lysates from collagen-stimulated platelets were incubated with GST-Grb2, suggesting that tyrosine phosphorylation of WASP may directly or indirectly modulate the adapter function of WASP. Although thrombin- and thrombopoietin-induced increase in tyrosine phosphorylation of WASP is negligible or marginal, WASP from thrombin-activated platelets became incorporated into the Triton X-100-insoluble 10, 000g sedimentable residue in an aggregation-dependent manner, suggesting that it may have a regulatory role in platelet cytoskeletal processes during aggregation. Lastly, we found that WASP is cleaved in response to activation of calpain, a protease that may have a role in postaggregation signaling processes. Our data suggest that collagen specifically induces an increase in tyrosine phosphorylation of WASP and that WASP is involved in signaling during thrombin-induced aggregation by its redistribution to the cytoskeleton and its cleavage during aggregation.
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PMID:Collagen induces tyrosine phosphorylation of Wiskott-Aldrich syndrome protein in human platelets. 973 Oct 41

Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms. We examined kidney pathology and collagen alpha 3 to alpha 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, alpha 3 to alpha 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen alpha 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen alpha 3 to alpha 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure. We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved alpha 3 to alpha 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded.
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PMID:Histopathology, ultrastructure, and clinical phenotypes in thin glomerular basement membrane disease variants. 1220 17

Collagen, the major macromolecular component of skin, is responsible for maintaining the structural integrity of the tissue as well as for providing important functional characteristics, such as pliability and thickness. We have been studying the structure and regulation of collagen in mouse mutations affecting the skin. In the course of these studies, we found that there are significant differences in collagen content between the skin of wild-type male and female mice, which become evident at puberty. Furthermore, male mice with an X-linked mutation in the androgen receptor gene (formerly called testicular feminization and abbreviated as Ar(Tfm)) showed decreased levels of collagen, indicating that the androgen receptor pathway contributes to the observed differences. These findings demonstrate that there are striking differences in the collagen content of skin between male and female mice, and provide a biochemical explanation for these differences.
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PMID:A role for the androgen receptor in collagen content of the skin. 1561 May 13

Collagen IV nephropathies (COL4Ns) comprise benign familial microscopic hematuria, thin basement membrane nephropathy (TBMN), X-linked Alport syndrome (AS) and also autosomal recessive and dominant AS. Apart from the X-linked form of AS, which is caused by hemizygous mutations in the COL4A5 gene, the other entities are caused by mutations in the COL4A3 or COL4A4 genes. The diagnosis of these conditions used to be based on clinical and/or histological findings of renal biopsies, but it is the new molecular genetics approach that revolutionised their investigation and proved particularly instrumental, especially, in many not so clear-cut cases. More recently, the spectrum of COL4N has expanded to include late onset focal segmental glomerulosclerosis (FSGS) that develops on top of TBMN in later life. Also, other reports showed that some patients with a primary diagnosis of familial FSGS proved to have variants in COL4 genes. In the presence of a renal biopsy picture of FSGS and in the absence of either electron microscopy studies or molecular genetic studies that point to TBMN and COL4N, the patient and his family may be mistakenly diagnosed with hereditary FSGS leading to unnecessary further investigations, erroneous family counselling and improper corticosteroid treatment. TBMN is a frequent finding in the general population, and according to several recent reports, it may be the underlying cause and the explanation for many familial and sporadic cases of late-onset FSGS with non-nephrotic proteinuria. This is an important new finding that needs widespread recognition. It is anticipated that the molecular genetic analysis with next generation sequencing will certainly offer timely correct diagnosis.
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PMID:Carriers of Autosomal Recessive Alport Syndrome with Thin Basement Membrane Nephropathy Presenting as Focal Segmental Glomerulosclerosis in Later Life. 2620 Dec 69