Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene.

Romeo, Giovani; Hammoud, Hassan; Staempfli, Susanne; Roncuzzi, Laura; Cianetti, L; Leonardi, Antonio; Vicente, Vicente; Pm, Mannucci; Bertina, R. M.; Peschle, Cesare

doi:10.1073/pnas.84.9.2829

Cited by 51 publications

(23 citation statements)

References 32 publications

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“…The variant c.del1212G, p.Gly404Glyfs17X was not previously described, while a frameshift in Trp342 leading to the same stop position as p.Gly343Alafs35X was previously reported [Reitsma et al, 1995]. Leu97X was not previously reported, while Cys120X was reported in a compound heterozygote (together with p. Asn371Thr) [Simioni et al, 1996] and Arg348X was associated (several times) mainly with type I deficiency [Romeo et al, 1987;Reitsma et al, 1995]. Finally, Glu71X was detected by us in a young girl who also carried two missense mutations, p.His108Asn and p.Ile213Thr (Table 2).…”

Section: Premature Stop Codonsmentioning

confidence: 92%

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C

Rovida¹,

Merati²,

D’Ursi³

et al. 2007

Hum. Mutat.

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Protein C (PC) is a key regulator of blood clotting and inflammation. Its inherited deficiency is associated with venous thromboembolism, and recombinant activated PC is currently used to increase survival in severe sepsis. The molecular basis of inherited PC deficiency is heterogeneous. Due to its multiple physiologic interactions and functions, and its modular structure, natural variants aid in the understanding of the relationship between critical residues and discrete functions. This knowledge has important therapeutic implications in the planning of a recombinant activated PC with a specific therapeutic target and devoid of major collateral effects. A way of predicting important functional consequences of residue variation is the use of molecular modeling and structural interpretation of amino acidic substitutions. A study of 21 out of 32 identified PC gene (PROC) variants is presented. For three of them, localized in the active site, electrostatic potential variation was calculated. For more than half of the studied variants, an explanation for the functional impairment could be derived from computational analysis, allowing a focused choice of which variants it is worthwhile pursuing.

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Section: Premature Stop Codonsmentioning

confidence: 92%

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C

Rovida¹,

Merati²,

D’Ursi³

et al. 2007

Hum. Mutat.

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“…Point mutations resulting from C -. T transitions have been documented in the Xlinked deficiencies of factors VIII and IX (68,69) as well as in autosomal disorders (70)(71)(72)(73)(74). Therefore, Msp I and Taq I were chosen for the initial screening of genomic DNA from the Fabry families.…”

Section: Discussionmentioning

confidence: 99%

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.

Bernstein¹,

Bishop²,

Astrin³

et al. 1989

J. Clin. Invest.

155

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Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, a-galactosidase. Southern hybridization analysis of the a-galactosidase gene in affected hemizygous males from 130 unrelated families with Fabry disease revealed six with different gene rearrangements and one with an exonic point mutation resulting in the obliteration of an Msp I restriction site. Five partial gene deletions were detected ranging in size from 0.4 to > 5.5 kb. Four of these deletions had breakpoints in intron 2, a region in the gene containing multiple Alu repeat sequences. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2 through 6, was duplicated by a homologous, but unequal crossover event. The Msp I site obliteration, which mapped to exon 7, was detected in an affected hemizygote who had residual enzyme activity. Genomic amplification by the polymerase chain reaction and sequencing revealed that the obliteration resulted from a C to T transition at nucleotide 1066 in the coding sequence. This point mutation, the first identified in Fabry disease, resulted in an arginine356 to tryptophan3% substitution which altered the enzyme's kinetic and stability properties. The detection of these abnormalities provided for the precise identification of Fabry heterozygotes, thereby permitting molecular pedigree analysis in these families which revealed paternity exclusions and the first documented new mutations in this disease.

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“…This indicates that heterozygous changes in these genes possibly have no early developmental consequences. Mutations in two of the affected genes-BANK1 and PROC-are associated with systemic lupus erythematosus (Kozyrev et al 2008) and thrombophilia (Romeo et al 1987), respectively. However, PROC and BANK1 duplications-as observed in our study-have not been reported to be associated with a clinical phenotype and the offspring carrying these de novo SVs appeared healthy at the time of sampling (aged 39 and 32).…”

Section: Functional Impact Of De Novo Structural Changesmentioning

confidence: 99%

Characteristics of de novo structural changes in the human genome

et al. 2015

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Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.

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Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene.

Cited by 51 publications

References 32 publications

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C

Identification and computationally-based structural interpretation of naturally occurring variants of human protein C

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.

Characteristics of de novo structural changes in the human genome

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