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TTC7A

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TTC7A
Identifiers
AliasesTTC7A, MINAT, TTC7, GIDID, tetratricopeptide repeat domain 7A
External IDsOMIM: 609332; MGI: 1920999; HomoloGene: 12515; GeneCards: TTC7A; OMA:TTC7A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57217

225049

Ensembl

ENSG00000068724

ENSMUSG00000036918

UniProt

Q9ULT0

Q8BGB2

RefSeq (mRNA)

NM_001288951
NM_001288953
NM_001288955
NM_020458

NM_028639

RefSeq (protein)

NP_001275880
NP_001275882
NP_001275884
NP_065191

NP_082915
NP_001391016
NP_001391017

Location (UCSC)Chr 2: 46.92 – 47.08 MbChr 17: 87.59 – 87.69 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tetratricopeptide repeat domain 7A (TTC7A) is a protein that in humans is encoded by the TTC7A gene.[5]

Function

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TPR domain-containing proteins, such as TTC7A, have diverse functions in cell cycle control, protein transport, phosphate turnover, and protein trafficking or secretion, and they can act as chaperones or scaffolding proteins.

Clinical significance

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TTC7A deficiency disrupts epithelial cell differentiation and polarization in the intestinal tract, thymus, and lungs. [6] TTC7A deficiency is very rare with less than 80 cases described in the literature to date.

Mutations in this gene are known to cause intestinal atresia, severe infantile or very early onset inflammatory bowel disease, extensive enteropathy, combined immunodeficiencies, thyroid dysfunction, alopecia, and lung disease. [7][8][9][10][11][12][13]

There is a broad spectrum of severity and variety of symptoms, although quality of life is generally very poor for these children with few surviving beyond the first year or two of life. [14]

Treatment

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There is no standard treatment for TTC7A Deficiency at this time. Management of TTC7A deficiency currently entails bowel resection for any atresias, hematopoietic stem cell transplantation to correct the immunodeficiencies and immunosuppression to help alleviate bowel disease and immune disregulation. However, Hematopoietic stem cell transplantation is ineffective for resolving the intestinal disease [15] Small bowel transplant has proven successful in at least one case.[16]

Rho Kinase Inhibitors

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Research indicates that TTC7A deficiency results in "increased Rho kinase activity which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development."[17] Based on this research, it has been proposed that Rho kinase inhibitors may be a therapeutic option, although no specific rho kinase inhibitors are currently available for patient use with the exception of Fasudil which is only available in Japan. It has been shown that statins such as Lipitor are useful as Rho kinase inhibitors.[18] Therefore, statins may be helpful for the treatment of TTC7A deficiency, although this has yet to be proven.

Recent research suggests that rho kinase inhibitors may be ineffective in treating TTC7A Deficiency. [19]

Leflunomide As Potential Treatment

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Recent research shows that Leflunomide reduces intestinal tract narrowing, restores gut motility, and increases intestinal cell survival in Zebrafish with TTC7A Deficiency. The researchers concluded that Leflunomide "might be repurposed for treatment of TTC7A deficiency."[20]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000068724 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036918 – Ensembl, May 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.
  5. ^ "Entrez Gene: Tetratricopeptide repeat domain 7A".
  6. ^ Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, et al. (January 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation. 124 (1): 328–337. doi:10.1172/JCI71471. PMC 3871247. PMID 24292712.
  7. ^ Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, et al. (September 2013). "Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias". The Journal of Allergy and Clinical Immunology. 132 (3): 656–664.e17. doi:10.1016/j.jaci.2013.06.013. PMC 3759618. PMID 23830146.
  8. ^ Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, et al. (May 2013). "Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia". Journal of Medical Genetics. 50 (5): 324–329. doi:10.1136/jmedgenet-2012-101483. PMC 3625823. PMID 23423984.
  9. ^ Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, et al. (April 2014). "Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease". Gastroenterology. 146 (4): 1028–1039. doi:10.1053/j.gastro.2014.01.015. PMC 4002656. PMID 24417819.
  10. ^ Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, et al. (December 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.
  11. ^ Ngan B, Merico D, Marcus N, Kim VH, Upton J, Bates A, et al. (May 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.
  12. ^ Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, Haddad E, et al. (December 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.
  13. ^ Agarwal NS, Northrop L, Anyane-Yeboa K, Aggarwal VS, Nagy PL, Demirdag YY (August 2014). "Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency". Journal of Clinical Immunology. 34 (6): 607–610. doi:10.1007/s10875-014-0067-7. PMID 24931897. S2CID 2421842.
  14. ^ Notarangelo LD (December 2014). "Multiple intestinal atresia with combined immune deficiency". Current Opinion in Pediatrics. 26 (6): 690–696. doi:10.1097/MOP.0000000000000159. PMID 25268403. S2CID 23342441.
  15. ^ Kammermeier J, Lucchini G, Pai SY, Worth A, Rampling D, Amrolia P, et al. (September 2016). "Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up". Blood. 128 (9): 1306–1308. doi:10.1182/blood-2016-01-696385. PMID 27418642. S2CID 206944245.
  16. ^ Gilroy RK, Coccia PF, Talmadge JE, Hatcher LI, Pirruccello SJ, Shaw BW, et al. (February 2004). "Donor immune reconstitution after liver-small bowel transplantation for multiple intestinal atresia with immunodeficiency". Blood. 103 (3): 1171–1174. doi:10.1182/blood-2003-04-1187. PMID 14525785.
  17. ^ Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, et al. (January 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation. 124 (1): 328–337. doi:10.1172/JCI71471. PMC 3871247. PMID 24292712.
  18. ^ Rentala S, Chintala R, Guda M, Chintala M, Komarraju AL, Mangamoori LN (November 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. PMID 24177008.
  19. ^ Jardine S, Anderson S, Babcock S, Leung G, Pan J, Dhingani N, et al. (March 2020). "Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency". Gastroenterology. 158 (4): 1000–1015. doi:10.1053/j.gastro.2019.11.019. PMC 7062591. PMID 31743734.
  20. ^ Jardine S, Anderson S, Babcock S, Leung G, Pan J, Dhingani N, et al. (March 2020). "Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency". Gastroenterology. 158 (4): 1000–1015. doi:10.1053/j.gastro.2019.11.019. PMC 7062591. PMID 31743734.
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