Biology:TTC7A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Tetratricopeptide repeat domain 7A (TTC7A) is a protein that in humans is encoded by the TTC7A gene.[1]

Function

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

TTC7A deficiency disrupts epithelial cell differentiation and polarization in the intestinal tract, thymus, and lungs. [2] 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. [3][4][5][6][7][8][9]

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. [10]

Treatment

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 [11] Small bowel transplant has proven successful in at least one case.[12]

Rho Kinase Inhibitors

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."[13] 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.[14] 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. [15]

Leflunomide As Potential Treatment

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."[16]

References

  1. ↑ "Entrez Gene: Tetratricopeptide repeat domain 7A". https://www.ncbi.nlm.nih.gov/gene/57217. 
  2. ↑ "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation 124 (1): 328–337. January 2014. doi:10.1172/JCI71471. PMID 24292712. 
  3. ↑ "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. September 2013. doi:10.1016/j.jaci.2013.06.013. PMID 23830146. 
  4. ↑ "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. May 2013. doi:10.1136/jmedgenet-2012-101483. PMID 23423984. 
  5. ↑ "Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease". Gastroenterology 146 (4): 1028–1039. April 2014. doi:10.1053/j.gastro.2014.01.015. PMID 24417819. 
  6. ↑ "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. December 2014. doi:10.1016/j.jaci.2014.07.019. PMID 25174867. 
  7. ↑ "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. May 2014. doi:10.14785/lpsn-2014-0002. 
  8. ↑ "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. December 2014. doi:10.1097/MD.0000000000000327. PMID 25546680. 
  9. ↑ "Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency". Journal of Clinical Immunology 34 (6): 607–610. August 2014. doi:10.1007/s10875-014-0067-7. PMID 24931897. 
  10. ↑ "Multiple intestinal atresia with combined immune deficiency". Current Opinion in Pediatrics 26 (6): 690–696. December 2014. doi:10.1097/MOP.0000000000000159. PMID 25268403. 
  11. ↑ "Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up". Blood 128 (9): 1306–1308. September 2016. doi:10.1182/blood-2016-01-696385. PMID 27418642. 
  12. ↑ "Donor immune reconstitution after liver-small bowel transplantation for multiple intestinal atresia with immunodeficiency". Blood 103 (3): 1171–1174. February 2004. doi:10.1182/blood-2003-04-1187. PMID 14525785. 
  13. ↑ "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation 124 (1): 328–337. January 2014. doi:10.1172/JCI71471. PMID 24292712. 
  14. ↑ "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. November 2013. doi:10.1016/j.bbrc.2013.10.112. PMID 24177008. 
  15. ↑ "Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency". Gastroenterology 158 (4): 1000–1015. March 2020. doi:10.1053/j.gastro.2019.11.019. PMID 31743734. 
  16. ↑ "Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency". Gastroenterology 158 (4): 1000–1015. March 2020. doi:10.1053/j.gastro.2019.11.019. PMID 31743734. 

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