User:Sandranith

DENND2C, also known as DENN/MADD domain containing 2C and RP5-1156J9.1, is a gene in humans that encodes a protein involved in important cellular processes. These processes include vesicle-mediated transport and the regulation of Rab GTPases, which are essential for various cell activities. DENND2C also plays a crucial role in the self-renewal of human embryonic stem cells and potentially, the normal function of the renal and urinary systems.

Gene
DENND2C is situated on chromosome 1 at the cytogenetic band 1p13.2 on the minus strand and spans 6177 base pairs. It comprises 21 exons and is found in the nucleoplasm. This gene has orthologs in a variety of species, such as birds, reptiles, mammals, amphibians, and fish. The genes AMPD1 and BCAS2 are located adjacent to DENND2C. DENND2A, DENND2B, and DENND2D are closely related paralogs of DENND2C.


 * Function: DENND2C is a member of the DENN (Differentially Expressed in Normal and Neoplastic cells) domain-containing protein family. These proteins regulate the activity of Rab GTPases and act as Rab-specific guanine nucleotide exchange factors (GEFs). DENND2C also interacts with NANOG and negatively regulates RHOA activity to block differentiation. It influences nuclear RHOA localization, activity, and DNA association.  An experiment conducted by the Wellcome Trust Sanger Institute involved inactivating the DENND2C gene in mice using Cre-lox recombination and showed that the knockout mice displayed abnormal urinary bladder morphology and bladder stones, indicating that DENND2C is necessary for normal renal and urinary system function.

The table to the right shows that DENND2C has three paralogs in humans,  DENND2A, DENND2B , and DENND2D. Sequence identity/similarity (excluding DENND2C ) are approximately: 43%/58%, 38%/51%, and 23%/33% respectively.

Protein
The primary protein isoform encoded by DENND2C, known as Q68D51-1, is 928 amino acids long and has a molecular mass of approximately 106,865 Daltons. There are also two alternative splicing variants :


 * Q68D51-2: This variant is missing amino acids 642-753.
 * Q68D51-3: This variant is missing amino acids 354-410.

The three-dimensional structure of DENND2C is predicted and can be viewed via AlphaFold. However, details about its quaternary structure are currently unavailable.

Orthologs
DENND2C has orthologs in a wide range of species, including birds, reptiles, mammals, amphibians, and fish. This broad conservation highlights its significant role across different organisms. The tabel to the right shows 20 orthologs of the DENND2C protein in different organisms, sorted by their median date of divergence and then by their sequence identity to the human protein. Fish are the most distantly related to human DENND2C, with the farthest divergence date of 462 million years ago and a sequence identity of 45%-53%. Mammals (excluding humans) are the closest, with a 81%-90% identity.

Reptiles have 67%-73%, birds 65%-68%, amphibians 63%-66%, and bony and cartilaginous fish 45%-53%. The only coelacanth with the protein is the West Indian Ocean coelacanth, with 58%.This data was gathered using NCBI BLAST, TimeTree, and EMBOSS NEEDLE.

Expression in Humans
DENND2C is most highly expressed in the esophagus and skin. It plays a role in guanyl-nucleotide exchange factor activity and is involved in the regulation of catalytic activity.

Diseases Associated with DENND2C:

 * Hypothyroidism, Congenital, Nongoitrous, 4: This condition results from mutations in DENND2C that affect thyroid hormone production.
 * Noonan Syndrome 6: Mutations in DENND2C that interfere with the RAS/MAPK signaling pathway cause this syndrome.

Evolutional History
The grpah on the right shows the Corrected Sequence Divergence VS Median Date of Divergence of DENND2C, Cytochrome C and Fibrinogen Alpha for humans, house mouse, green sea turtle, chicken, and clown anemonefish.

Fibrinogen alpha (dark gray line) changes the fastest, with about 190 amino acid changes after 200 million years. DENND2C (light gray line) changes moderately, about 30 times, and Cytochrome C (green line) changes the slowest, only about 10 times at the same mya.

This tells us that cytochrome c stays similar over time (highly conserved) but fibrinogen alpha changes a lot (less conserved). The graph supports the idea that genetic changes happen steadily over time (linear), as predicted by the molecular clock hypothesis.