Loss-of-Function Variants in CCDC189 Cause Human Oligoasthenoteratozoospermia by Disrupting Sperm Flagellar and...

Oligoasthenoteratozoospermia (OAT), characterized by reduced sperm count, impaired motility, and abnormal morphology, is a major cause of male infertility with substantial genetic heterogeneity. However, the underlying genetic etiology remains unresolved in a large proportion of affected individuals.

This study aimed to identify novel genetic causes of human OAT and to investigate the molecular and clinical consequences of the identified variants.

Whole-exome sequencing was performed in infertile men diagnosed with severe OAT. Identified variants were evaluated by population database screening and functional analyses, including quantitative mRNA assessment, label-free proteomics, immunofluorescence staining, and transmission electron microscopy (TEM). Clinical outcomes following assisted reproductive treatment were also documented.

We identified CCDC189 as a novel pathogenic gene associated with human OAT. Two unrelated infertile men carried homozygous variants in CCDC189, including a frameshift variant (c.709_711del, p.W237Afs*3) and a missense variant (c.898C>T, p.R300W), both of which were rare in population databases. Clinically, both individuals exhibited severe OAT with profound acrosomal abnormalities and multiple morphological defects of the sperm flagella. TEM analysis revealed acrosomal detachment, cytoplasmic retention, loss of radial spokes, and absence of the central pair complex, indicating severe disruption of axonemal architecture. Consistently, CCDC189 mRNA levels were markedly reduced, and proteomic and immunofluorescence analyses confirmed the loss of CCDC189 protein along with its interacting partner CABCOCO1. Despite severe structural abnormalities, intracytoplasmic sperm injection (ICSI) using ejaculated sperm from one patient resulted in normal fertilization, high-quality embryo development, and an ongoing clinical pregnancy.

Our findings establish CCDC189 as a pathogenic gene underlying human OAT and expand the spectrum of coiled-coil domain-containing proteins essential for sperm morphogenesis. The favorable ICSI outcome underscores the clinical importance of genetic diagnosis in CCDC189-related infertility and supports ICSI as an effective therapeutic option for affected couples.