Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia.
Mutations in POLR3A (OMIM #614258) are associated with 4H leukodystrophy syndrome characterized by the triad of hypomyelination, hypodontia, and hypogonadotrophic hypogonadism.
POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism.
A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B.
Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome).
Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.
Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex.