TTC7A

TTC7A
Identifikatori
Aliasi	TTC7A
Vanjski ID-jevi	OMIM: 609332 MGI: 1920999 HomoloGene: 12515 GeneCards: TTC7A
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	47,076,137 bp
Lokacija gena (miš)
Hrom.	Hromosom 17 (miš)
Kraj	87,689,197 bp
Ortolozi
	57217
	225049
	ENSG00000068724
	ENSMUSG00000036918
	Q9ULT0
	Q8BGB2
	NM_001288951; NM_001288953; NM_001288955; NM_020458
	NM_028639
	NP_001275880; NP_001275882; NP_001275884; NP_065191
	NP_082915; NP_001391016; NP_001391017
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Tetratrikopeptid-ponavljajući domen 7A (TTC7A) jest protein koji je kod ljudi kodiran genom TTC7A sa hromosoma 2.^[5]

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 858 aminokiselina, a molekulska težina 96.185 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MAAKGAHGSY	LKVESELERC	RAEGHWDRMP	ELVRQLQTLS	MPGGGGNRRG
SPSAAFTFPD	TDDFGKLLLA	EALLEQCLKE	NHAKIKDSMP	LLEKNEPKMS
EAKNYLSSIL	NHGRLSPQYM	CEAMLILGKL	HYVEGSYRDA	ISMYARAGID
DMSMENKPLY	QMRLLSEAFV	IKGLSLERLP	NSIASRFRLT	EREEEVITCF
ERASWIAQVF	LQELEKTTNN	STSRHLKGCH	PLDYELTYFL	EAALQSAYVK
NLKKGNIVKG	MRELREVLRT	VETKATQNFK	VMAAKHLAGV	LLHSLSEECY
WSPLSHPLPE	FMGKEESSFA	TQALRKPHLY	EGDNLYCPKD	NIEEALLLLL
ISESMATRDV	VLSRVPEQEE	DRTVSLQNAA	AIYDLLSITL	GRRGQYVMLS
ECLERAMKFA	FGEFHLWYQV	ALSMVACGKS	AYAVSLLREC	VKLRPSDPTV
PLMAAKVCIG	SLRWLEEAEH	FAMMVISLGE	EAGEFLPKGY	LALGLTYSLQ
ATDATLKSKQ	DELHRKALQT	LERAQQLAPS	DPQVILYVSL	QLALVRQISS
AMEQLQEALK	VRKDDAHALH	LLALLFSAQK	HHQHALDVVN	MAITEHPENF
NLMFTKVKLE	QVLKGPEEAL	VTCRQVLRLW	QTLYSFSQLG	GLEKDGSFGE
GLTMKKQSGM	HLTLPDAHDA	DSGSRRASSI	AASRLEEAMS	ELTMPSSVLK
QGPMQLWTTL	EQIWLQAAEL	FMEQQHLKEA	GFCIQEAAGL	FPTSHSVLYM
RGRLAEVKGN	LEEAKQLYKE	ALTVNPDGVR	IMHSLGLMLS	RLGHKSLAQK
VLRDAVERQS	TCHEAWQGLG	EVLQAQGQNE	AAVDCFLTAL	ELEASSPVLP
FSIIPREL

Funkcija

Proteini koji sadrže TPR domen, kao što je TTC7A, imaju različite funkcije u kontroli ćelijskog ciklusa, transportu proteina, prometu fosfata i prometu ili sekreciji proteina, a mogu djelovati i kao šaperoni ili proteini skele.

Klinički značaj

Nedostatak TTC7A remeti diferencijaciju i polarizaciju epitelnih ćelija u crijevnom traktu, timusu i plućima.^[7] Nedostatak TTC7A je vrlo rijedak, do danas s manje od 80 slučajeva opisanih u literaturi.

Poznato je da mutacije ovog gena uzrokuju crijevnu atreziju, tešku dojenačku ili vrlo rani početak upalne bolesti crijeva, opsežnu enteropatiju, kombinirane imunodeficijencije, disfunkciju štitnjače, alopeciju i bolesti pluća.^[8]^[9]^[10]^[11]^[12]^[13]^[14]

Postoji širok spektar ozbiljnosti i raznolikosti simptoma, iako je kvalitet života ove djece općenito vrlo loš, a samo nekoliko njih preživi nakon prve ili dvije godine života.^[15]

Tretman

Još ne postoji standardni tretman za nedostatak TTC7A. Upravljanje nedostatkom TTC7A uključuje resekciju crijeva za bilo koju atreziju, transplantaciju hematopoetskih matičnih ćelija za korekciju imunodeficijencije i imunosupresiju, kako bi se ublažila bolest crijeva i imunoska disregulacija. Međutim, transplantacija hematopoetskih matičnih ćelija nije efikasna za rješavanje crijevne bolesti ^[16] Transplantacija tankog crijeva se pokazala uspješnom u najmanje jednom slučaju.^[17]

Inhibitori Rho kinaze

Istraživanja pokazuju da nedostatak TTC7A rezultira "povećanom razinom Rho-kinaza, aktivnošću koja remeti polarnost, rast i diferencijaciju crijevnih epitelnih ćelija, koja narušava homeostazu imunskih ćelija, čime se podstiče razvoj MIA-CID."^[18] Na osnovu ovog istraživanja, predloženo je da inhibitori Rho kinaze mogu biti terapijska opcija, iako još nisu dostupni specifični inhibitori rho-kinaze za pacijente s izuzetkom Fasudila koji je dostupan samo u Japanu. Pokazalo se da su statini kao što je Lipitor korisni kao inhibitori Rho-kinaze.^[19] Zato statini mogu biti od pomoći u liječenju nedostatka TTC7A, iako to tek treba biti dokazano.

Nedavna istraživanja sugeriraju da inhibitori rho-kinaze mogu biti neučinkoviti u liječenju nedostatka TTC7A.^[20]

Leflunomid kao potencijalni lijek

Nedavna istraživanja pokazuju da Leflunomid smanjuje sužavanje crijevnog trakta, vraća pokretljivost crijeva i povećava preživljavanje crijevnih čelija kod zebrica s nedostatkom TTC7A. Istraživači su zaključili da bi Leflunomid "mogao biti prenamijenjen za liječenje nedostatka TTC7A."^[20]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000068724 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000036918 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Entrez Gene: Tetratricopeptide repeat domain 7A".
^ "UniProt, Q9ULT0" (jezik: engleski). Pristupljeno 15. 11. 2021.
^ Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, Schulz A, Philippet P, Schlesser P, Abrahamsen TG, Oymar K, Davies EG, Ellingsen CL, Leteurtre E, Moreau-Massart B, Berrebi D, Bole-Feysot C, Nischke P, Brousse N, Fischer A, Clevers H, de Saint Basile G (Jan 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation (jezik: engleski). 124 (1): 328–37. doi:10.1172/JCI71471. PMC 3871247. PMID 24292712.
^ Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, et al. (2013). "Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias". J. Allergy Clin. Immunol. 132 (3): 656–664.e17. doi:10.1016/j.jaci.2013.06.013. PMC 3759618. PMID 23830146.
^ Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, et al. (2013). "Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia". J. Med. Genet. 50 (5): 324–9. doi:10.1136/jmedgenet-2012-101483. PMC 3625823. PMID 23423984.
^ Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, et al. (2014). "Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease". Gastroenterology. 146 (4): 1028–39. doi:10.1053/j.gastro.2014.01.015. PMC 4002656. PMID 24417819.
^ Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, Héritier S, Lemale J, Talbotec C, Rieux-Laucat F, Ruemmele F, Morali A, Cathebras P, Nitschke P, Bole-Feysot C, Blanche S, Brousse N, Picard C, Clevers H, Fischer A, de Saint Basile G (2014). "Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency". The Journal of Allergy and Clinical Immunology. 134 (6): 1354–1364.e6. doi:10.1016/j.jaci.2014.07.019. PMID 25174867.
^ Ngan, Bo (maj 2014). "Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia". LymphoSign Journal. 1 (1): 10–26. doi:10.14785/lpsn-2014-0002.
^ Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, Haddad E, Decaluwe H, Le Deist F (Dec 2014). "Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort". Medicine. 93 (29): e327. doi:10.1097/MD.0000000000000327. PMC 4602622. PMID 25546680.
^ Agarwal NS, Northrop L, Anyane-Yeboa K, Aggarwal VS, Nagy PL, Demirdag YY (2014). "Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency". Journal of Clinical Immunology. 34 (6): 607–10. doi:10.1007/s10875-014-0067-7. PMID 24931897. S2CID 2421842.
^ Notarangelo LD (2014). "Multiple intestinal atresia with combined immune deficiency". Curr. Opin. Pediatr. 26 (6): 690–6. doi:10.1097/MOP.0000000000000159. PMID 25268403. S2CID 23342441.
^ "Validate User".
^ Gilroy RK, Coccia PF, Talmadge JE, Hatcher LI, Pirruccello SJ, Shaw BW, Rubocki RJ, Sudan DL, Langnas AN, Horslen SP (Feb 2004). "Donor immune reconstitution after liver-small bowel transplantation for multiple intestinal atresia with immunodeficiency". Blood. 103 (3): 1171–4. doi:10.1182/blood-2003-04-1187. PMID 14525785.
^ Bigorgne, Amélie E.; Farin, Henner F.; Lemoine, Roxane; Mahlaoui, Nizar; Lambert, Nathalie; Gil, Marine; Schulz, Ansgar; Philippet, Pierre; Schlesser, Patrick; Abrahamsen, Tore G.; Oymar, Knut; Davies, E. Graham; Ellingsen, Christian Lycke; Leteurtre, Emmanuelle; Moreau-Massart, Brigitte; Berrebi, Dominique; Bole-Feysot, Christine; Nischke, Patrick; Brousse, Nicole; Fischer, Alain; Clevers, Hans; De Saint Basile, Geneviève (2. 1. 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". Journal of Clinical Investigation (jezik: engleski). 124 (1): 328–337. doi:10.1172/JCI71471. PMC 3871247. PMID 24292712.
^ Rentala, Satyanarayana; Chintala, Ramakrishna; Guda, Manohar; Chintala, Madhuri; Komarraju, Aruna Lakshmi; Mangamoori, Lakshmi Narasu (22. 11. 2013). "Atorvastatin inhibited Rho-associated kinase 1 (ROCK1) and focal adhesion kinase (FAK) mediated adhesion and differentiation of CD133+CD44+ prostate cancer stem cells". Biochemical and Biophysical Research Communications. 441 (3): 586–592. doi:10.1016/j.bbrc.2013.10.112. ISSN 1090-2104. PMID 24177008.
^ ^a ^b Sasha, Jardine (2020). "Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Diseases Caused by TTC7A Deficiency". Gastroenterology. 158 (4): 1000–1015. doi:10.1053/j.gastro.2019.11.019. PMC 7062591. PMID 31743734. Pristupljeno 18. 11. 2019.

Vanjski linkovi

TTC7A protein, human na US National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000068724 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000036918 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: Tetratricopeptide repeat domain 7A".

[UniProt-6] "UniProt, Q9ULT0" (jezik: engleski). Pristupljeno 15. 11. 2021.

[7] Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, Schulz A, Philippet P, Schlesser P, Abrahamsen TG, Oymar K, Davies EG, Ellingsen CL, Leteurtre E, Moreau-Massart B, Berrebi D, Bole-Feysot C, Nischke P, Brousse N, Fischer A, Clevers H, de Saint Basile G (Jan 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation (jezik: engleski). 124 (1): 328–37. doi:10.1172/JCI71471. PMC 3871247. PMID 24292712.

[pmid23830146-8] Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, et al. (2013). "Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias". J. Allergy Clin. Immunol. 132 (3): 656–664.e17. doi:10.1016/j.jaci.2013.06.013. PMC 3759618. PMID 23830146.

[pmid23423984-9] Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, et al. (2013). "Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia". J. Med. Genet. 50 (5): 324–9. doi:10.1136/jmedgenet-2012-101483. PMC 3625823. PMID 23423984.

[pmid24417819-10] Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, et al. (2014). "Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease". Gastroenterology. 146 (4): 1028–39. doi:10.1053/j.gastro.2014.01.015. PMC 4002656. PMID 24417819.

[pmid25174867-11] Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, Héritier S, Lemale J, Talbotec C, Rieux-Laucat F, Ruemmele F, Morali A, Cathebras P, Nitschke P, Bole-Feysot C, Blanche S, Brousse N, Picard C, Clevers H, Fischer A, de Saint Basile G (2014). "Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency". The Journal of Allergy and Clinical Immunology. 134 (6): 1354–1364.e6. doi:10.1016/j.jaci.2014.07.019. PMID 25174867.

[12] Ngan, Bo (maj 2014). "Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia". LymphoSign Journal. 1 (1): 10–26. doi:10.14785/lpsn-2014-0002.

[13] Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, Haddad E, Decaluwe H, Le Deist F (Dec 2014). "Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort". Medicine. 93 (29): e327. doi:10.1097/MD.0000000000000327. PMC 4602622. PMID 25546680.

[pmid24931897-14] Agarwal NS, Northrop L, Anyane-Yeboa K, Aggarwal VS, Nagy PL, Demirdag YY (2014). "Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency". Journal of Clinical Immunology. 34 (6): 607–10. doi:10.1007/s10875-014-0067-7. PMID 24931897. S2CID 2421842.

[pmid25268403-15] Notarangelo LD (2014). "Multiple intestinal atresia with combined immune deficiency". Curr. Opin. Pediatr. 26 (6): 690–6. doi:10.1097/MOP.0000000000000159. PMID 25268403. S2CID 23342441.

[16] "Validate User".

[17] Gilroy RK, Coccia PF, Talmadge JE, Hatcher LI, Pirruccello SJ, Shaw BW, Rubocki RJ, Sudan DL, Langnas AN, Horslen SP (Feb 2004). "Donor immune reconstitution after liver-small bowel transplantation for multiple intestinal atresia with immunodeficiency". Blood. 103 (3): 1171–4. doi:10.1182/blood-2003-04-1187. PMID 14525785.

[18] Bigorgne, Amélie E.; Farin, Henner F.; Lemoine, Roxane; Mahlaoui, Nizar; Lambert, Nathalie; Gil, Marine; Schulz, Ansgar; Philippet, Pierre; Schlesser, Patrick; Abrahamsen, Tore G.; Oymar, Knut; Davies, E. Graham; Ellingsen, Christian Lycke; Leteurtre, Emmanuelle; Moreau-Massart, Brigitte; Berrebi, Dominique; Bole-Feysot, Christine; Nischke, Patrick; Brousse, Nicole; Fischer, Alain; Clevers, Hans; De Saint Basile, Geneviève (2. 1. 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". Journal of Clinical Investigation (jezik: engleski). 124 (1): 328–337. doi:10.1172/JCI71471. PMC 3871247. PMID 24292712.

[19] Rentala, Satyanarayana; Chintala, Ramakrishna; Guda, Manohar; Chintala, Madhuri; Komarraju, Aruna Lakshmi; Mangamoori, Lakshmi Narasu (22. 11. 2013). "Atorvastatin inhibited Rho-associated kinase 1 (ROCK1) and focal adhesion kinase (FAK) mediated adhesion and differentiation of CD133+CD44+ prostate cancer stem cells". Biochemical and Biophysical Research Communications. 441 (3): 586–592. doi:10.1016/j.bbrc.2013.10.112. ISSN 1090-2104. PMID 24177008.

[gastrojournal.org-20] Sasha, Jardine (2020). "Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Diseases Caused by TTC7A Deficiency". Gastroenterology. 158 (4): 1000–1015. doi:10.1053/j.gastro.2019.11.019. PMC 7062591. PMID 31743734. Pristupljeno 18. 11. 2019.

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