DNAH3 – Male Infertility

Dynein axonemal heavy chain 3 (DNAH3) is a core component of the inner dynein arm (IDA) of sperm flagella and is highly expressed in the testis. Male infertility (MONDO:0005372) often manifests as asthenozoospermia or asthenoteratozoospermia due to defective axonemal proteins. Initial reports have not clarified DNAH3’s role in human infertility.

Recessive inheritance of biallelic DNAH3 variants was identified in four unrelated Han Chinese men with asthenoteratozoospermia through whole-exome sequencing. These patients carried two predicted loss-of-function alleles, c.5587del (p.Ser1863LeufsTer9) and c.4837G>T (p.Gly1613Ter), resulting in negligible DNAH3 expression in sperm flagella (4 probands) PMID:39503742. No familial segregation beyond probands was reported.

Ultrastructural analysis of patient spermatozoa revealed severe disruption of IDA architecture and mitochondrial sheath abnormalities, correlating with absent DNAH3 immunostaining. These defects mirror the asthenoteratozoospermia phenotype (HP:0007280, HP:0001977).

In a Dnah3 knockout mouse model, male mice were infertile with profoundly reduced sperm motility, aberrant IDA and mitochondrial morphology, and decreased levels of IDA-associated proteins DNAH1, DNAH6, and DNALI1. Fertility was restored by intracytoplasmic sperm injection (ICSI), confirming a loss-of-function mechanism PMID:39503742.

An independent study of two OAT patients identified additional biallelic DNAH3 mutations, including a premature stop codon c.10122G>A (p.Trp3374Ter), which led to reduced mRNA and protein levels and MMAF phenotypes, further supporting pathogenicity via protein truncation PMID:39588341.

Collectively, autosomal recessive loss of DNAH3 impairs IDA assembly and sperm flagellar function. DNAH3 should be included in diagnostic gene panels for male infertility, enabling genetic counseling and personalized assisted-reproduction strategies.

References

• Journal Unknown • 2024 • Axonemal protein complexes, including the outer and inner dynein arms drive sperm motility and DNAH3 deficiency underlies asthenoteratozoospermia in humans and mice PMID:39503742
• Frontiers in Endocrinology • 2024 • Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia. PMID:39588341

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