The more selective transport of proline and other imino acids is driven at the molecular level by a mammalian cellular transport mechanism aptly known as system IMINO. While no single genetic mutation has been established as the cause of iminoglycinuria; several mutations, affecting transport mechanisms shared by glycine, proline and hydroxyproline, as well as those that selectively transport either glycine or imino acids, including the IMINO system, are known to be associated with the disorder. When combined, these factors will result in a variable phenotype for iminoglycinuria depending on which mutations are present. However, despite the role that intestinal malabsorption of glycine and imino acids can play in iminoglycinuria, the primary defect disrupts their renal transport and reabsorption. This is evident, as inherited iminoglycinuria can be clinically present with no intestinal involvement.In mammals, including humans, the transport of amino and imino acids from the lumen (interior) of the intestine or the renal proximal tubule into the cells occurs at the brush border membrane of the epithelium (moist, tightly packed cellular lining of many tissues and organs of the body). Here, cotransporters such as sodium or chloride (part of the system of Na-K-Cl cotransporters) couple with the amino or imino acids on the molecular level and transport them through specific integral membrane proteins that form ion channels, which are located within the cell membrane. From the cells, the absorbed or reabsorbed amino and imino acids eventually reach the blood.
As absorption and reabsorption of glycine, proline and hydroxyproline occurs through PAT1 as well, it is believed to play another role in expressing the malabsorptive iminoglycinuria phenotype. Recent reports, however, suggest a more diminished role from PAT1 in some cases of the disorder.While PAT2 is strongly indicated as the primary mutagen responsible for iminoglycinuria, the variability of the phenotype is found to be instituted by three modifying genetic mutations. The major one among these is believed to be system IMINO.Defined as the sodium-dependent proline transporter not inhibited by alanine, system IMINO, believed to be formed by the SLC6A20 (SIT1) gene, is a crucial mammalian transport mechanism responsible for both renal reabsorption and intestinal absorption of proline and other imino acids, such as hydroxyproline and pipecolate. The mRNA sequence for SIT1 is expressed in a great deal of the gastrointestinal tract, including the stomach, duodenum, jejunum, ileum, cecum and colon. It is also found in the kidney, optical choroid, and parts of the central nervous system such the brain and microglial cells.Reduced penetrance is a phenomenon where a fully inherited genetic trait, such as a disease or disorder, fails to exhibit the expected phenotype. This has been reported in some cases of iminoglycinuria. Here, system IMINO is thought to play a role in reduced penetrance of iminoglycinuria by compensating for imino acid malabsorption related specifically to mutations of PAT2.