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)

Human biglycan is a small proteoglycan that is expressed at high levels in the growing skeleton and in human skin at the cell surface of differentiating keratinocytes. The human gene for biglycan (BGN) has previously been mapped by in situ hybridization to the Xq27-q28 region. Employing somatic hybrid cell lines with human X chromosome breakpoints within this region, we performed a fine mapping of the gene within Xq28. Our results indicate that the biglycan gene is proximal to the red/green cone pigment genes, G6PD, and coagulation factor VIII and is distal to DXS304, DXS305, and GABRA3. The biglycan gene precisely maps to a region of the X chromosome, where, by comparative gene mapping, one would expect to find the gene for X-linked dominant chondrodysplasia punctata/ichthyosis/short stature (Happle) syndrome. Hence, BGN is a candidate gene for the Happle syndrome.
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PMID:Fine mapping of the human biglycan (BGN) gene within the Xq28 region employing a hybrid cell panel. 161 9

We are using pulsed-field gel electrophoresis (PFGE) to establish a physical map of the human Xq28 region. We have identified a new probe 35.239 (DXYS64), localized in Xq28 by somatic hybrid mapping and belonging to a region of greater than 99% homology between the X and the Y chromosomes. PFGE data show that probes 35.239 and the polymorphic locus DXS115 (probe 767) map within a common 300-kb BssHII fragment. Both probes, in addition, hybridize to 575-kb BssHII and 590-kb ClaI fragments that contain the gene coding for coagulation factor VIII (F8C). The order F8C-DXS115-DXYS64 could be determined. Our results also provide evidence for linkage between the red/green color vision locus (RCP,GCP) and probes MD13 and T1.7 (GdX, DXS254) within a 750-kb ClaI fragment. Although the latter two probes are located within 50 kb of the 3' end of the G6PD gene, a G6PD cDNA probe did not hybridize to this fragment. G6PD, on the other hand, could be linked to F8C on a 290-kb BssHII fragment. All these data allow us to propose the order (RCP,GCP)-MD13-GdX-G6PD-F8C-DXS115-DXYS 64. We also linked probes St14 (DXS52), MN12 (DXS33), and DX13 (DXS15) to a member of a small family of X-linked dispersed sequences (DNF22S3) within a 575-kb BssHII fragment. The preliminary physical map presented here should be useful for further fine mapping of disease genes in the Xq28 region and should be helpful in orientating efforts toward the cloning of sequences close to the fragile X syndrome.
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PMID:Toward a physical map of the Xq28 region in man: linking color vision, G6PD, and coagulation factor VIII genes to an X-Y homology region. 250 Dec 12

Hemophilia A is an X-linked bleeding disorder resulting from a defect in coagulation factor VIII. Clinical severity, the level of factor VIII activity and coagulant antigen vary widely. However, the three parameters breed true in families, indicating that the phenotypic expression directly reflects the genetic defect. In about 5%, hemophilia A results from partial deletion of the factor VIII gene and is clinically severe. In another 5% single base mutations have been found, which destroy the binding sites for the restriction enzyme TaqI. They can be "nonsense" mutations resulting in stop codons and clinically severe hemophilia, or "missense" mutations resulting in amino acid changes and milder forms of hemophilia. By the use of the polymerase chain reaction and denaturing gradient gel electrophoresis we have detected several point mutations. The formation of anti-factor VIII antibodies appears to be more frequent in patients with defects resulting in absence of factor VIII protein. Carrier detection and prenatal diagnosis can be made with 100% certainty in families with identified mutations. In their absence, polymorphisms affecting recognition sequences for 2 restriction enzymes (BclI and XbaI) within or outside the factor VIII gene can serve as a tag for the mutation and be followed through the pedigree. In the absence of any informative polymorphism the conventional methods for carrier detection are still helpful.--In roughly 1/3 of the patients, the mutation appears "sporadic". However, it can usually be traced within one or two generations of the proband. --Some patients have mosaicism for sporadic mutations, indicating that mutagenesis not necessarily occurs at the level of the gametes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular genetics of hemophilia A. 250 18

Using restriction fragment length polymorphisms (RFLPs) and enzymatic variants between distantly related mouse species, we have assigned three genes to the mouse X chromosome and concurrently mapped a total of eight genes spanning an estimated 50 cM of the chromosome. Segregation of RFLPs in over 200 male progeny from interspecies backcrosses between the inbred strain C57BL/6JRos and either wild-derived Mus musculus or Mus spretus was followed for the murine genes Timp (tissue inhibitor of metalloproteinases), Cf-8 (coagulation factor VIII), and Rsvp (red-sensitive visual pigment) and the known X-linked markers Otc, Hprt, Cf-9, G6pd, and Ags. From the centromere, the gene order was defined as Otc, Timp, Hprt, Cf-9, (Cf-8/Rsvp/G6pd), Ags, by minimizing the number of multiple recombinational events. No significant differences in map order or frequency of recombination were observed between the two backcross series studied. The use of Southern analysis has allowed us to add new genes to the map in a cumulative manner, and as probes become available, additional markers can be mapped, using the same set of mice, by utilizing existing blots or resampling the DNAs. The use of probes for functional genes has allowed us to directly compare the X chromosomes of mouse and man and has provided insight into chromosomal rearrangements which have occurred during the evolutionary divergence of these species, as well as to define the extent of linkage homologies.
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PMID:Multilocus molecular mapping of the mouse X chromosome. 290 27

Haemophilia A is a classic X-linked disease which affects 1 in 5-10,000 males in all populations and is caused by defects in coagulation factor VIII. Roughly 60% of patients have severe disease with factor VIII activity < 1% of normal; they have frequent spontaneous bleeding into joints, soft tissues, muscles and internal organs. These patients usually require regular injections of plasma-derived or recombinant human factor VIII. Because this is expensive and can potentially lead to life-threatening complications, other forms of therapy, including gene therapy, have been proposed. Natural canine models of factor VIII and factor IX deficiency have been available for many years, and gene therapy attempts on these dogs have met with partial success. However, a small animal model of the disease is desirable for studies of factor VIII function and gene therapy. Using gene targeting, we have made a mouse with severe factor VIII deficiency.
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PMID:Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. 764 82

Haemophilia A is an X-linked bleeding disorder caused by mutations in the coagulation factor VIII (FVIII) gene. The identification and characterization of naturally occurring disease-producing mutations allows the recognition of new mechanisms of pathogenesis in haemophilia A. Analysis of the illegitimately transcribed FVIII mRNA in a severely affected patient has revealed that the A-->G transition at position -2 of the acceptor splice site of intron 4 results in the skipping of exon 5 in 90% of the processed pre-mRNA. Another minor mRNA species arising from the skipping of exons 4 and 5 has also been observed. The skipping of exon 5 predicts the removal of the corresponding 13 amino acids from the A1 domain of FVIII. A novel missense mutation, C329S, in exon 8 of FVIII gene has been identified in another patient.
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PMID:Characterization of a splicing mutation in the factor VIII gene at the RNA level. 781 12

Hemophilia A is an X-linked bleeding disorder caused by a quantitative or qualitative defect of coagulation factor VIII. Since factor VIII has been cloned and several intragenic and linked DNA polymorphisms discovered, DNA analysis is an accepted and commonly used method for carrier testing in hemophilia A. Both a direct method using detection of mutation and an indirect method based on linkage between the disease and DNA polymorphism are used for this purpose. In this study, DNA samples of 110 hemophilia A patients from 99 families were screened for factor VIII gene mutation using Southern blot analysis; in seven families, mutations were detected. In 13 females from six families with identified mutation, the direct diagnosis of carriers was performed. Four intragenic (BclI, XbaI, BglI and MspI in F8C locus) and two linked polymorphisms (TaqI in DXS52 locus and BglII in DXS15 locus) were studied in members of 47 hemophilia A families. BclI-XbaI-BglI haplotypes were analyzed in 90 unrelated X chromosomes. Eighteen out of 31 females (58%) were heterozygous for at least one intragenic polymorphism, and 29 out of 31 females (94%) were heterozygous for at least one intra- or extragenic polymorphism tested. Carrier diagnosis was made in 15 out of 25 possible carriers (60%) based on intragenic and in an additional 3 out of 25 (12%) only on linked polymorphism.
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PMID:Factor VIII gene mutations and RFLP analysis in hemophilia A. 810 Apr 65

Bloch-Sulzberger incontinentia pigmenti (IP) is a rare X-linked neuroectodermal syndrome. Over 97% of the patients are female. We report on a male baby who developed blisters in linear groups or bands shortly after birth. When the child was 3 months old the blisters were followed by verrucous papules, which cleared after 1 year leaving areas of brownish grey hyperpigmentation. In addition to the skin involvement, our patient showed central motor dysfunction on the right side of the body and also dental and ocular anomalies. Both parents were in good health. Chromosome analysis yielded a normal karyotype (46, XY). The genes for coagulation factor VIII and biglycan in the Xq28 region were not deleted. The presence of the disease in this male infant may be due to an early somatic mutation or a half-chromatid mutation. A further possibility is mosaic expression of an unstable premutation. This model offers a good explanation for the reports in the literature of transmission of the disease from mother to son.
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PMID:[Incontinentia pigmenti in a male infant]. 827 92

The differential diagnosis of the genetic bleeding disorders, hemophilia A and von Willebrand disease, is occasionally confounded by the close molecular relationship of coagulation factor VIII and von Willebrand factor (vWF). This report describes the autosomal inheritance of a hemophilia A phenotype due to a mutation of vWF that results in defective factor VIII binding. The proband was a female patient with low levels of factor VIII activity. Polymerase chain reaction (PCR) amplification and DNA sequencing were employed to examine exons encoding the putative factor VIII binding domain of vWF. The patient was found to be homozygous for a single point mutation causing a Thr-->Met substitution at amino acid position 28 in the mature vWF subunit. The phenotypic expression of the mutation was determined to be recessive because heterozygous family members were clinically unaffected. Recombinant vWF containing the observed amino acid substitution was expressed in COS-1 cells. The mutant vWF was processed and secreted normally, and was functionally equivalent to wild-type vWF in its ability to bind to platelets. However, the mutant failed to bind factor VIII, demonstrating that the mutation was functionally related to the observed hemophilia phenotype. The family we describe demonstrates the recessive inheritance of a recently recognized class of genetic bleeding disorders, we call "autosomal hemophilia." We conclude that vWF mutation may be an under recognized cause of hemophilia, especially in cases where the inheritance pattern is not consistent with X-linked transmission.
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PMID:Autosomal recessive transmission of hemophilia A due to a von Willebrand factor mutation. 850 Jul 91

Myxoid heart disease is frequently encountered in the general population. It corresponds to an etiologically heterogeneous group of diseases, idiopathic mitral valve prolapse (IMVP) being the most common form. A rarely observed form of myxoid heart disease, X-linked myxomatous valvular dystrophy (XMVD), is inherited in an X-linked fashion and is characterized by multivalvular myxomatous degeneration; however, the histopathological features of the mitral valve do not differ significantly from the severe form of IMVP. In this article, we describe the genetic analysis of a large family in which XMVD is associated with a mild hemophilia A. The coagulation factor VIII gene position in Xq28 provided a starting point for the genetic study, which was conducted by use of polymorphic markers. Two-point linkage analysis confirmed this localization, and a maximum LOD score of 6.57 was found at straight theta=0 for two polymorphic microsatellite markers, INT-3 and DXS1008, the first one being intronic to the factor VIII gene. Haplotype analysis of this chromosomal region allowed the definition of an 8-cM minimal interval containing the gene for XMVD, between DXS8011 and Xqter.
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PMID:Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28. 949 44


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