A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis

Area of Science:

• Human Genetics
• Reproductive Biology
• Molecular Medicine

Background:

• Large-headed multi-tailed spermatozoa is a rare male infertility phenotype with a poor prognosis.
• Previous studies linked this phenotype to homozygous mutations in the Aurora Kinase C (AURKC) gene, causing meiotic arrest and tetraploid sperm.
• AURKC deficiency results in non-functional sperm unsuitable for fertilization.

Purpose of the Study:

• To investigate the genetic basis of large-headed spermatozoa in two brothers.
• To determine if mutations in the AURKC gene are responsible for the observed phenotype in these patients.
• To refine diagnostic approaches for male infertility associated with this sperm morphology.

Main Methods:

• Molecular analysis of the AURKC gene, including complete gene sequencing.
• Analysis of AURKC transcripts using reverse transcription polymerase chain reaction (RT-PCR).
• Identification and characterization of novel genetic variants within the AURKC gene.

Main Results:

• Both affected brothers were heterozygous for the previously identified c.144delC mutation.
• A new heterozygous splice site variant (c.436-2A>G) in exon 5 of the AURKC gene was identified in both patients.
• RT-PCR confirmed that the c.436-2A>G variant leads to exon 5 skipping and a truncated AURKC transcript.

Conclusions:

• AURKC molecular analysis in patients with large-headed spermatozoa should include complete gene sequencing, not just screening for the common exon 3 mutation.
• The identification of AURKC mutations is critical, as it implies all resulting spermatozoa are chromosomally abnormal.
• Patients diagnosed with AURKC mutations should not undergo intracytoplasmic sperm injection (ICSI) due to the high likelihood of fertilization failure and chromosomal abnormalities.