Creatine transport deficiency is a fairly common genetic disease (X-linked) that causes mental retardation and seizures.
Males are mostly those affected because males have only a single X-chromosome, so males only have a single creatine transporter gene (SLC6A8). A single spontaneous mutation in SLC6A8, therefore, can cause the disease.
I made homology models of human creatine transporter to view a particular mutation in SLC6A8, a tryptophan to arginine substitution (W402–>R402). The creatine transporter model was based on a Drosophila melanogaster (fruit fly) dopamine transporter. I used the online server Phyre2 to generate the model.
The W402–>R402 mutation is located in a highly conserved hydrophobic residue located at the membrane-solvent interface. Arginine is positively charged and hydrophilic, so the substitution may cause the transporter not to settle properly in the membrane, which is a hydrophobic environment. This mutation causes a partial defect in creatine transport but can cause severe symptoms.
Humans require creatine transport to obtain enough creatine in the brain and muscles, tissues that do not make enough of their own creatine. Brain and muscle require a lot of creatine to support high cellular energy requirements. Creatine is utilized to ensure that brain and muscle have sufficient ATP to support the high metabolism rates. Creatine is utilized in the recharging of ADP to ATP.
