F9 variant is not secreted

Stable Identifier
Reaction [transition]
Homo sapiens
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In healthy individuals, the coagulation factor IX (FIX) is synthesized as a 461 amino acid precursor (primarily in the liver) and then secreted into plasma where it converts factor X to its active form. FIX zymogen undergoes extensive co- and post-translational modifications, including but not limited to glycosylation and γ-carboxylation. A deficiency or dysfunction of FIX caused by mutations in the F9 gene is associated with a blood clotting disorder hemophilia B (HB). The FIX protein level may be decreased in the circulation by F9 mutations affecting FIX protein synthesis, stability, or secretion. The carboxyl-terminal region of FIX contains several natural missense mutations such as Y450C, W453R and T458K, which impair secretion of FIX and result in mild to severe forms of HB (Kurachi S et al. 1997; Branchini A et al. 2013). In addition, exon 5 of the F9 gene contains dense splicing regulatory information that overlap with the amino acid code (Tajnik M et al. 2016). Under normal conditions exon 5 is correctly recognized by the spliceosome and mostly included in the final transcript. This leads to the production of a normal FIX protein that folds correctly in the endoplasmic reticulum (ER) and is efficiently secreted into the blood to activate coagulation. Several F9 mutations in exon 5 result in exon skipping (Tajnik M et al. 2016; Odaira K et al. 2019; Katneni UK et al. 2019). The exonic splicing mutations (ESM) can be divided into three major groups which define their molecular basis. In the first group, two synonymous variants, V153V and R162R, affect binding of splicing factors and induce severe exon skipping with the production of a non-functional mRNA (Tajnik M et al. 2016). The second type of ESM, such as A164V and Q167H, showed partial splicing defects producing low amounts of normally spliced transcript that, when translated, resulted in a defective FIX protein with a significantly reduced, but not completely abolished, secretion. However, the lower amounts of the secreted proteins maintained a normal specific coagulant activity. Lastly, mutation L163F (ESM group 3) showed a splicing defect but the resulting amino acid change severely affected FIX secretion (Tajnik M et al. 2016). Another HB-associated F9 variant caused abnormal mRNA splicing, r.83_88del, and produced the mutant FIX protein (p.C28_V30delinsF), which is an in-frame mutant at the signal peptide cleavage site (Odaira K et al. 2019). The FIX C28_V30delinsF variant was found to be retained in the ER without being secreted (Odaira K et al. 2019). Studies also showed defective secretion of HB-associated F9 nonsense mutations such as R294*, R298* and R384* (Branchini A et al. 2017; Pinotti M et al. 2012). The mechanism through which nonsense mutations impair gene expression and cause human genetic disease consists of premature translation termination, and the synthesis of truncated proteins with loss‐of‐function features (Mort M et al. 2008). These mutations can trigger nonsense‐mediated decay of mRNA, that degrades mRNA transcripts that harbor a premature translation-termination codon (PTC), thus reducing the synthesis of truncated proteins (Khajavi et al. 2006; Kurosaki T & Maquat LE 2016). However, the mechanism of ribosome readthrough, which consists of misrecognition of the premature stop codon by an aminoacyl‐tRNA instead of the termination factors can restore translation impaired by nonsense mutations (Rospert S et al. 2005). The occurrence of spontaneous ribosome readthrough over F9 R294* and F9 R298* nonsense mutations led to the synthesis of traces of full‐length FIX in HB patients (Pinotti M et al. 2012). A drug-induced ribosome readthrough targeting nonsense variants is considered as a potential treatment of inherited coagulation factor disorders (Branchini A et al. 2017; Ferrarese M et al. 2018; Balestra D & Branchini A 2019).

The Reactome event describes intracellular accumulation and/or decreased secretion of FIX due to different HB-related genetic alterations spread throughout the F9 gene. The F9 variants are described in relation to changes in the protein sequence. Defective splicing events induced by F9 mutations are not shown here.

Literature References
PubMed ID Title Journal Year
27227676 Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function

Barbon, E, Tajnik, M, Pinotti, M, Pagani, F, Balestra, D, Bussani, E, Rogalska, ME

PLoS Genet. 2016
28007939 Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B

Komar, AA, Sauna, ZE, Monroe, DM, Jha, S, Hamasaki-Katagiri, N, Simhadri, VL, Zhu, L, Wu, A, Tseng, SC, Lin, BC, Kimchi-Sarfaty, C, Peters, R, Freedberg, DI, Zichel, R, Lu, Q, Bentley, AA, Hunt, R

J. Med. Genet. 2017
22618954 Ribosome readthrough accounts for secreted full-length factor IX in hemophilia B patients with nonsense mutations

Campioni, M, Caruso, P, Castaman, G, Pinotti, M, Bernardi, F, Belvini, D, Canella, A, Giacomelli, S, Tagariello, G

Hum. Mutat. 2012
29993188 The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation

Bernardi, F, Pignani, S, Todaro, A, Pinotti, M, Marchi, S, Pinton, P, Balestra, D, Lombardi, S, Ferrarese, M, Branchini, A

J. Thromb. Haemost. 2018
23994528 Replacement of the Y450 (c234) phenyl ring in the carboxyl-terminal region of coagulation factor IX causes pleiotropic effects on secretion and enzyme activity

Biondo, F, Campioni, M, Bicocchi, MP, Mazzucconi, MG, Pinotti, M, Branchini, A, Bernardi, F, Mari, R

FEBS Lett. 2013
31102861 Apparent synonymous mutation F9 c.87A>G causes secretion failure by in-frame mutation with aberrant splicing

Tamura, S, Matsushita, T, Suzuki, A, Kojima, T, Hayakawa, F, Tokoro, M, Suzuki, N, Suzuki, S, Katsumi, A, Odaira, K, Hattori, Y, Kakihara, M, Kanematsu, T, Okamoto, S, Takagi, A

Thromb. Res. 2019
28196793 Specific factor IX mRNA and protein features favor drug-induced readthrough over recurrent nonsense mutations

Campioni, M, Castaman, G, Pinotti, M, Ferrarese, M, Branchini, A, Bernardi, F, Mari, R

Blood 2017
9100030 The carboxyl-terminal region of factor IX is essential for its secretion

Kurachi, K, Pantazatos, DP, Kurachi, S

Biochemistry 1997
15219198 Two novel mutations in EGF-like domains of human factor IX dramatically impair intracellular processing and secretion

Rodriguez, MH, Vinciguerra, C, Enjolras, N, Rea, M, Negrier, C, Attali, O, Plantier, JL

J. Thromb. Haemost. 2004
Normal reaction
Functional status

Loss of function of Non-secretable F9 variant [endoplasmic reticulum lumen]

Name Identifier Synonyms
hemophilia B DOID:12259 factor IX deficiency, Congenital factor IX deficiency, deficiency, functional factor IX, Congenital factor IX disorder
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