A new in silico approach to investigate molecular aspects of factor IX missense causative mutations and their impact on the hemophilia B severity
Abstract Factor IX (encoded by F9) is a protein in the coagulation process, where its lack or deficiency leads to hemophilia B. This condition has been much less studied than hemophilia A, especially in Latin America. We analyzed the structural and functional impact of 54 missense mutations (18 reported by us previously, and 36 other mutations from the Factor IX database) through molecular modeling approaches. To accomplish this task, we examine the electrostatic patterns, hydrophobicity/hydrophilicity, disulfide, and H‐bond differences of the Factor IX structures harboring the missense mutations found, correlating them with their clinical effects. The 54 mutated sequences were modeled and their physicochemical features were determined and used as input in clusterization tools. The electrostatic pattern seems to influence in disease severity, especially for mutations investigated in epidermal growth factors 1 and 2 (EGF1/2) domains. The combined use of all physicochemical information improved the clustering of structures associated to similar phenotypes, especially for mutations from GLA and EGF1–2 domains. The effect of mutations in the disease phenotype severity seems to be a complex interplay of molecular features, each one contributing to different impacts. This highlights that previous studies and tools analyzing individually single features for single mutations are missing elements that fulfill the whole picture..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
|---|---|
| Enthalten in: |
Human mutation - 40(2019), 6, Seite 706-715 |
| Beteiligte Personen: |
Meireles, Mariana R. [VerfasserIn] |
|---|
| BKL: |
|---|
| Anmerkungen: |
© 2019 Wiley Periodicals, Inc. |
|---|
| Umfang: |
10 |
|---|
| doi: |
10.1002/humu.23733 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
WLY007178271 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | WLY007178271 | ||
| 003 | DE-627 | ||
| 005 | 20230307165411.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230216s2019 xx |||||o 00| ||und c | ||
| 024 | 7 | |a 10.1002/humu.23733 |2 doi | |
| 028 | 5 | 2 | |a HUMU_HUMU23733.xml |
| 035 | |a (DE-627)WLY007178271 | ||
| 035 | |a (WILEY)HUMU23733 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 082 | 0 | 4 | |a 570 |a 610 |q ASE |
| 084 | |a 44.48 |2 bkl | ||
| 100 | 1 | |a Meireles, Mariana R. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A new in silico approach to investigate molecular aspects of factor IX missense causative mutations and their impact on the hemophilia B severity |
| 264 | 1 | |c 2019 | |
| 300 | |a 10 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © 2019 Wiley Periodicals, Inc. | ||
| 520 | |a Abstract Factor IX (encoded by F9) is a protein in the coagulation process, where its lack or deficiency leads to hemophilia B. This condition has been much less studied than hemophilia A, especially in Latin America. We analyzed the structural and functional impact of 54 missense mutations (18 reported by us previously, and 36 other mutations from the Factor IX database) through molecular modeling approaches. To accomplish this task, we examine the electrostatic patterns, hydrophobicity/hydrophilicity, disulfide, and H‐bond differences of the Factor IX structures harboring the missense mutations found, correlating them with their clinical effects. The 54 mutated sequences were modeled and their physicochemical features were determined and used as input in clusterization tools. The electrostatic pattern seems to influence in disease severity, especially for mutations investigated in epidermal growth factors 1 and 2 (EGF1/2) domains. The combined use of all physicochemical information improved the clustering of structures associated to similar phenotypes, especially for mutations from GLA and EGF1–2 domains. The effect of mutations in the disease phenotype severity seems to be a complex interplay of molecular features, each one contributing to different impacts. This highlights that previous studies and tools analyzing individually single features for single mutations are missing elements that fulfill the whole picture. | ||
| 700 | 1 | |a Bragatte, Marcelo A.S. |4 aut | |
| 700 | 1 | |a Bandinelli, Eliane |4 aut | |
| 700 | 1 | |a Salzano, Francisco M. |4 aut | |
| 700 | 1 | |a Vieira, Gustavo F. |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Human mutation |d New York, NY [u.a.] : Wiley-Liss, 1992 |g 40(2019), 6, Seite 706-715 |w (DE-627)WLY007177046 |w (DE-600)1498165-8 |x 10981004 |7 nnns |
| 773 | 1 | 8 | |g volume:40 |g year:2019 |g number:6 |g pages:706-715 |g extent:10 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_WLY | ||
| 936 | b | k | |a 44.48 |q ASE |
| 951 | |a AR | ||
| 952 | |d 40 |j 2019 |e 6 |h 706-715 |g 10 | ||