PRDX1 gene

Variants (also known as mutations) in the PRDX1 gene are involved in methylmalonic acidemia with homocystinuria, epi-cblC type (shortened to epi-cblC), which is one form of a disorder that causes developmental delay, eye defects, neurological problems, and blood abnormalities. 

Variants in the PRDX1 gene cause epi-cblC by leading to a genetic change called promoter hypermethylation. (This genetic change is also called an epimutation). The promoter is a region of DNA near a gene that controls gene activity (expression). Hypermethylation occurs when too many small molecules called methyl groups are attached to the promoter region. PRDX1 gene variants involved in epi-cblC alter the DNA in such a way that the promoter of the nearby MMACHC gene becomes hypermethylated. The extra methyl groups reduce the expression of the MMACHC gene, which means that less MMACHC protein is produced.

People with epi-cblC with a PRDX1 gene variant on one copy of the chromosome usually have an MMACHC gene variant on the other copy. (Very rarely, an affected individual has  a PRDX1 gene variant on both copies of the chromosome and no MMACHC gene variant.) As a result, cells make little to no functional MMACHC protein. A reduction in this protein's function prevents normal processing of vitamin B12. This vitamin is usually converted to two important molecules. A shortage of both molecules leads to the signs and symptoms of methylmalonic acidemia with homocystinuria. 

Research suggests that PRDX1 gene variants may also lead to hypermethylation of other gene promoters. It is unclear if reduced expression of other genes plays a role in the development of epi-cblC. In addition, the effect of PRDX1 gene variants on the production or function of the peroxiredoxin-1 protein is unclear. More studies are needed to understand if hypermethylation of additional promoters or changes to peroxiredoxin-1 contribute to methylmalonic acidemia with homocystinuria or cause additional signs or symptoms in affected individuals.