Polymorphism in the multi-phosphorylation domain of the human neurofilament heavy-subunit-encoding gene

The C-terminal region of the human neurofilament heavy subunit (NEFH) contains a unique functional domain consisting of 43 repeat motifs of the amino acids (aa) Lys-Ser-Pro (KSP) with either 3- or 5-aa spacers in between. Past studies have demonstrated that the serine in these KSP motifs can be phosphorylated, resulting in heavy phosphorylation of this domain. Recent studies provide strong evidence for a role of neurofilament phosphorylation in the establishment of neurofilament density and axonal caliber. Since it may be hypothesized that mutations in the phosphorylated region are a basis for neuropathological conditions, and since regions of the human genome containing repeat motifs have been demonstrated to be significantly polymorphic, we undertook to identify and characterize polymorphism in this region of the human NEFH gene. We were able to identify an allelic variant of a slightly larger molecular size, containing an additional KSP phosphorylation motif. The variant form of NEFH displays Mendelian inheritance and has a widespread population distribution. In addition, we also identified a point mutation in one individual which would result in a Pro-->Leu substitution in one of the repeat motifs.