Factor XSanto Domingo. Evidence that the severe clinical phenotype arises from a mutation blocking secretion.

Watzke, Herbert; Wallmark, Anders; Hamaguchi, Nobuko; Giardina, Patricia J.; Stafford, DW; High, KA

doi:10.1172/jci115484

Cited by 37 publications

(26 citation statements)

References 34 publications

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“…28 For the wild-type construct, levels of F.IX in the media were in the range of 536 ng/mL to 776 ng/mL at 96 hours (mean ϭ 696 ng/mL), and levels in the cell lysate were approximately 40 ng/mL to 190 ng/mL (mean ϭ 115 ng/mL; Table 2). Levels of F.IX antigen secreted into the media were undetectable for the ES, LS, and cCH variants, and similar to wild-type for the MS mutation.…”

Section: Resultsmentioning

confidence: 99%

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Sabatino

Armstrong

Edmonson

et al. 2004

Blood

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Animal models have been critical to the development of novel therapeutics in hemophilia. A deficiency of current murine models of hemophilia B is that they are all due to gene deletions, a type of mutation that is relatively rare in the human hemophilia population. We generated mice with a range of mutations in the Factor IX (F.IX) gene; these more faithfully reflect the types of mutations that cause disease in the human population. Transgenic mice expressing either wild-type human F.IX (hF.IX), or F.IX variants with premature translation termination codons, or missense mutations, under the control of the murine transthyretin promoter, were generated and crossed with mice carrying a large deletion of the murine F.IX gene. Gene copy number, F.IX transcript levels in the liver, intrahepatocyte protein expression, and circulating levels of F.IX protein in the mice were determined and compared with data generated by transient transfection assays using the same F.IX variants. Mice were injected with a viral vector expressing hF.IX and displayed a range of immune responses to the transgene product, depending on the underlying mutation. These new mouse models faithfully mimic the mutations causing human disease, and will prove useful for testing novel therapies for hemophilia.

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Section: Resultsmentioning

confidence: 99%

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Sabatino

Armstrong

Edmonson

et al. 2004

Blood

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“…This mutation at amino acid position -8 blocks targeting and/or cleavage by signal peptidase of the nascent preproparathyroid hormone and thus blocks secretion of the mature hormone. In the second example, a severe bleeding diathesis is caused by the substitution of Arg for Gly at amino acid position -3 of the signal peptide of coagulation Factor X ( 12). The afflicted patient has a severe deficiency of Factor X which is caused by the failure of signal peptidase to cleave the mutant Factor Xsanto Domingo ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

“…An amino acid substitution within the hydrophobic core of the signal peptide of preproparathyroid hormone has been linked to a form offamilial hypoparathyroidism (11). Similarly, a severe bleeding diathesis results from a substitution at the -3 position of the signal peptide of coagulation Factor Xsnto Domingo ( 12,13). In each case, the alteration of the signal peptide structure results in the failure to secrete the affected protein.…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of inefficient cleavage of preprovasopressin by signal peptidase as a cause for familial central diabetes insipidus.

Ito

Oiso²,

Murase³

et al. 1993

J. Clin. Invest.

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A transition of G to A at nucleotide position 279 in exon 1 ofthe vasopressin gene has been identified in patients with familial central diabetes insipidus. The mutation predicts an amino acid substitution of Thr (ACG) for Ala (GCG) at the COOH terminus of the signal peptide in preprovasopressin (preproVP). Translation in vitro of wild-type and mutant mRNAs produced 19-kD preproVPs. When translated in the presence of canine pancreatic rough microsomes, wild-type preproVP was converted to a 21-kD protein, whereas the mutant mRNA produced proteins of 21 kD and 23 kD. NH2-terminal amino acid sequence analysis revealed that the 21-kD proteins from the wild-type and the mutant were proVPs generated by the proteolytic cleavage of the 19-residue signal peptide and the addition of carbohydrate. Accordingly, mutant preproVP was cleaved at the correct site after Thr-19, but the efficiency of cleavage by signal peptidase was < 25% that observed for the wild-type preproVP, resulting in the formation of a predominant glycosylated but uncleaved 23-kD product. These data suggest that inefficient processing of preproVP produced by the mutant allele is possibly involved in the pathogenesis of diabetes insipidus in the affected individuals. (J. Clin. Invest. 1993. 91:2565-2571

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“…In some instances-as, for example, due to missense mutations in the genes of fibrinogen, 13 FVII, 14 FX, 15 and FXI 16 -mutant proteins are produced normally but ultimately not secreted because impaired folding and/or conformational changes cause their retention by the quality control system of the secretory pathway, eventually leading to intracellular degradation or accumulation. [13][14][15] In others, the mutant recombinant protein is fully secreted, so that it is possible to compare in vitro the abnormal functional properties with those of the wild-type protein and to understand the nature of the defect and sometimes the mechanism of the corresponding bleeding tendency. [17][18][19] A previous review article listed all the gene mutations identified for each RICD until 2002.…”

Section: Expression Studiesmentioning

confidence: 99%

“…4,15,[43][44][45][46][47] Phenotypically, most affected individuals have low but measurable levels of FX activity, 44 suggesting that the complete absence of FX in plasma may be incompatible with adult life. Another feature of FX deficiency is the complete absence of reported nonsense mutations, 4 whereas a small number of deletions leading to stop codons were identified (Table 3).…”

Section: Fx Deficiencymentioning

confidence: 99%

Erratum for vol. 104, p. 526

2004

Blood

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Deficiencies of coagulation factors other than factor VIII and factor IX that cause bleeding disorders are inherited as autosomal recessive traits and are rare, with prevalences in the general population varying between 1 in 500 000 and 1 in 2 million for the homozygous forms. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not as well established as for hemophilia A and B. We investigated more than 1000 patients with recessively inherited coagulation disorders from Italy and Iran, a country with a high rate of recessive diseases due to the custom of consanguineous marriages.Based upon this experience, this article reviews the genetic basis, prevalent clinical manifestations, and management of these disorders. The steps and actions necessary to improve the condition of these often neglected patients are out-

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Factor XSanto Domingo. Evidence that the severe clinical phenotype arises from a mutation blocking secretion.

Cited by 37 publications

References 34 publications

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Possible involvement of inefficient cleavage of preprovasopressin by signal peptidase as a cause for familial central diabetes insipidus.

Erratum for vol. 104, p. 526

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