Biallelic Truncating Variant in LRGUK Is Associated With Severe Multiple Morphological Abnormalities of the Sperm Flagella and Sperm Nuclear Defects in Humans.

Homozygous truncating variant in LRGUK (c.1063C>T; p.Arg355Ter) predicted to remove the C-terminal guanylate kinase-like domain, with absence of LRGUK protein in patient spermatozoa and altered central apparatus-associated proteins.

Multiple morphological abnormalities of the flagella (MMAF) is a severe form of male infertility in which many cases remain genetically unexplained. The authors identify a homozygous truncating variant in LRGUK (c.1063C>T; p.Arg355Ter) in an infertile man with a typical MMAF phenotype, found by whole-exome sequencing in a cohort of 168 MMAF patients and confirmed by Sanger sequencing. Immunofluorescence showed absence of LRGUK protein in the patient's spermatozoa, supporting loss of function, with impaired motility and complete teratozoospermia. Morphological and ultrastructural analyses revealed severe head and flagellum defects, including disorganised axonemal architecture and central pair abnormalities, while nuclear analyses showed increased nuclear size, defective chromatin compaction and elevated DNA fragmentation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A single patient, but a complete functional case — absent protein, ultrastructure, nuclear involvement — that makes the LRGUK–MMAF link credible from this first human description. The clinically most interesting detail is the combination of a nuclear defect, with DNA fragmentation, and the flagellar phenotype: this shifts the discussion towards ICSI prognosis and not only the diagnostic label. Replication in other infertility cohorts remains essential before reporting this gene in routine practice.

Analysis by Dr Thibaut Benquey