Tetratricopeptide repeat domain 7A (TTC7A) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''TTC7A''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

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. 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 Intestinal atresia is any congenital malformation of the structure of the intestine that causes bowel obstruction. The malformation can be a narrowing (stenosis), absence or malrotation of a portion of the intestine. These defects can either occur ...

, severe infantile or very early onset

inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...

, extensive

enteropathy Enteropathy refers to any pathology of the intestine. Although enteritis specifically refers to an inflammation of the intestine, and is thus a more specific term than "enteropathy", the two phrases are sometimes used interchangeably. __TOC__ Type ...

combined immunodeficiencies Combined immunodeficiencies (or combined immunity deficiency) are immunodeficiency disorders that involve multiple components of the immune system, including both humoral immunity and cell-mediated immunity. This category includes conditions su ...

, thyroid dysfunction, alopecia, and lung disease. 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.

Treatment

There is no standard treatment for TTC7A Deficiency at this time. Management of TTC7A deficiency currently entails

bowel resection A bowel resection or enterectomy ('' enter-'' + '' -ectomy'') is a surgical procedure in which a part of an intestine (bowel) is removed, from either the small intestine or large intestine. Often the word ''enterectomy'' is reserved for the sense ...

for any atresias,

hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...

to correct the immunodeficiencies and immunosuppression to help alleviate bowel disease and immune disregulation. However,

Hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...

is ineffective for resolving the intestinal disease Small bowel transplant has proven successful in at least one case.

Rho Kinase Inhibitors

Research indicates that TTC7A deficiency results in "increased

Rho kinase Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton. ROCKs ( ...

activity which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development." Based on this research, it has been proposed that

Rho kinase inhibitor Rho-kinase inhibitors (rho-associated protein kinase inhibitor or ROCK inhibitor) are a series of compounds that target rho kinase (ROCK) and inhibit the ROCK pathway. Clinical trials have found that inhibition of the ROCK pathway contributes to the ...

s may be a therapeutic option, although no specific rho kinase inhibitors are currently available for patient use with the exception of

Fasudil Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen ...

which is only available in Japan. It has been shown that statins such as Lipitor are useful as Rho kinase inhibitors. 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.

Leflunomide As Potential Treatment

Recent research shows that

Leflunomide Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibito ...

reduces intestinal tract narrowing, restores gut motility, and increases intestinal cell survival in Zebrafish with TTC7A Deficiency. The researchers concluded that

"might be repurposed for treatment of TTC7A deficiency."

References

External links

* {{MeshName, TTC7A+protein,+human Human proteins