A homozygous RNF220 mutation leads to male infertility with small-headed sperm.

Morphological abnormality of spermatozoa head is a human infertility syndrome caused by spermatogenesis defects. The genetic alterations associated with macrozoospermia, globozoospermia and acephalic spermatozoa are relatively definite, whereas the underlying pathogenesis of small-headed sperm remains unclear. Here, we report a 32-year-old infertile male from a consanguineous family, who presented with 95% of small-headed sperm. Subsequent whole-exome sequencing (WES) analysis identified a homozygous mutation (c. 56C>T [p. P19L]) in Ring Finger Protein 220 (RNF220) gene, which is dominantly expressed in testis. RNF220 protein is an E3 ligase promoting the ubiquitination and proteasomal degradation of SIN3 Transcription Regulator Family Member B (SIN3B), a chromatin-associated protein, which is primarily expressed in the nucleus of germ cells and plays a vital role in chromatin condensation. Notably, this variant could promote the RNF220 protein degradation leading to excessive condensed chromatin in the sperm through the medium SIN3B. Therefore, our study is the first to identify an autosomal recessive genetic mutation in RNF220 that was responsible for small-headed sperm in humans by regulating the expression of chromatin-associated protein SIN3B.