Deregulation of sperm nuclear
protamine ratio (P1/P2) has been shown to correlate with male factor
infertility in humans, but the cause of this abnormal
protein expression has yet to be identified. Recent studies have shown that there is little genetic variability in the coding regions of either of the
protamine gene sequences. However, these studies did not investigate the 5' or 3' non-coding regions of these genes for mutations that might account for changes in the transcriptional or translational regulation of the
protamines. In an effort to determine if genetic variation in these non-coding regions may account for aberrant
protamine expression, we have sequenced the 5' and
3' untranslated regions (
UTRs) of both
protamine 1 (P1) and
protamine 2 (P2) genes in a population of infertile men with
protamine deregulation, men presenting for
infertility work-up with normal
protamine ratios, and a population of unrelated, fertile men from the Utah Genetic Reference Project (UGRP). This analysis has identified 14 single nucleotide polymorphisms (SNPs), of which 13 were novel SNPs in the
UTRs of P1 and P2, and verified the existence of a variable length repeat (VLR), GAn, in the P2 5' region. The SNP frequencies and VLR allelic frequencies did not achieve statistical significance between the populations, however, one of the SNPs identified in the
3' UTR of
protamine 2 was found at a low frequency in the abnormal
protamine patients, but was completely absent in men with verified normal
protamine ratio and donors of known fertility. In conclusion, a number of SNPs have been reported in the
protamine genes and the
untranslated regions, however, these gene variants do not appear to be responsible for
protamine deficiency. Hence, the underlying cause for aberrant
protamine expression may possibly be due to abnormalities in candidate spermatogenic transcriptional/translational regulators, post-translational modifiers, or as-of-yet unidentified factors affecting the testicular environment.