Jan 2026· Human Mutation· Vol 2026· 0 citations· 53 references
Medicine
TL;DR
Findings confirm ARL2BP as a causative gene for both PCD and MMAF, expanding the genotypic and phenotypic spectrum of ciliopathies and recommending long‐term ophthalmological follow‐up to detect delayed‐onset retinal degeneration.
Abstract
Primary ciliary dyskinesia (PCD) and multiple morphological abnormalities of the sperm flagella (MMAF) frequently co‐occur in male infertility. However, the genetic basis of this syndromic presentation remains unclear. Using whole‐exome sequencing, we identified a novel homozygous ARL2BP splice‐site mutation (c.294‐2A>G) in a 23‐year‐old infertile male from a consanguineous family who presented with syndromic PCD and MMAF. This variant causes aberrant pre‐mRNA splicing and triggers nonsense‐mediated mRNA decay, resulting in the complete absence of ARL2BP protein expression. Transmission electron microscopy revealed extensive disorganization of flagellar axonemes with consistent central pair (CP) microtubule depletion and disorganization of peripheral doublets. Immunofluorescence confirmed a severe deficiency of the CP protein SPAG6 in the sperm flagella. Notably, the patient presented without retinal symptoms. Given that ARL2BP‐related retinitis pigmentosa generally emerges during the third decade, long‐term ophthalmological follow‐up is essential to detect delayed‐onset retinal degeneration. In conclusion, these findings confirm ARL2BP as a causative gene for both PCD and MMAF, expanding the genotypic and phenotypic spectrum of ciliopathies.
Multiple morphological abnormalities of the flagella (MMAF) is a severe form of male infertility characterized by immotile spermatozoa with absent, short, coiled, or irregular flagella. Despite advances in whole-exome sequencing, many cases remain genetically unexplained. Here, we identify a homozygous truncating variant in LRGUK (c.1063C>T; p.Arg355Ter) in an infertile man presenting with a typical MMAF phenotype. The variant, identified by whole-exome sequencing in a cohort of 168 MMAF patients and confirmed by Sanger sequencing, is predicted to result in loss of the C-terminal guanylate kinase-like domain. Immunofluorescence showed absence of LRGUK protein in patient spermatozoa, supporting a loss-of-function effect. Semen analysis revealed impaired motility and complete teratozoospermia. Morphological and ultrastructural analyzes demonstrated severe defects affecting both sperm head and flagellum, including disorganized axonemal architecture and central pair abnormalities. Nuclear analyzes showed increased nuclear size, defective chromatin compaction, and elevated DNA fragmentation. Immunostaining further indicated alterations of central apparatus-associated proteins, supporting a role for LRGUK in C1b projection organization. These findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly.
Wiâme Mokkedem, Zeinab Wehbe, A. Barbotin et al.· Clinical Genetics· 0 citations
Multiple morphological abnormalities of the sperm flagella (MMAF) represent a severe form of asthenozoospermia that leads to male infertility, and it is commonly associated with genetic defects affecting flagellar components. Although the gene CFAP65 has been implicated in MMAF, its full mutational spectrum and clinical relevance within highly consanguineous populations remain poorly characterized. To elucidate the genetic basis of this condition, whole-exome sequencing followed by Sanger sequencing was performed in two infertile individuals from a consanguineous Pakistani family. Sperm morphology was assessed using hematoxylin-eosin (H&E) staining; while scanning and transmission electron microscopy (SEM and TEM) were utilized to evaluate ultrastructural defects. A novel homozygous frameshift mutation in CFAP65 (c.582_587delinsCG; p.Q194Hfs*4) was identified. This mutation introduces a premature stop codon within the transmembrane helix domain. Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm. TEM further demonstrated severe axonemal disorganization, with absent or disrupted microtubule doublets observed in 85% of the cross-sections. Based on clinical history and chest X-ray, the affected individuals reported no chronic respiratory symptoms and had no situs inversus, suggesting an isolated sperm-specific phenotype. In conclusion, this study identifies a novel domain-specific CFAP65 mutation associated with MMAF and male infertility in a consanguineous Pakistani family, thereby expanding the known genetic mutational landscape of MMAF. These findings reinforce the crucial role of CFAP65 in sperm flagellar morphogenesis and underscore its significance in the genetic diagnosis of male infertility.
Musavir Abbas, Ansar Hussain, Ma Hui et al.· Basic and Clinical Andrology· 0 citations
Plasma proteomic analysis of patients with CILD40 identified significant enrichment of pathways related to platelet activation, complement and coagulation cascades and differential signatures in CILD40, highlighting the potential of plasma proteomics for understanding distinct pathogenic mechanisms across PCD subtypes.
Siming Kong, Mingshuo Wang, Xuedong Wang et al.· Phenomics· 0 citations
ABSTRACT Primary ciliary dyskinesia (PCD) is a clinical syndrome that in dogs primarily manifests as chronic respiratory disease associated with cilial malfunction. The current study employs whole‐genome sequencing and a candidate gene approach to uncover the genetic basis of PCD in three Cocker Spaniel siblings following diagnosis of their respiratory cilia by scanning electron microscopy and high‐speed video microscopy. Absence of the disorder in the parents suggested autosomal recessive inheritance. A 29 bp frameshift insertion in the eleventh exon of the candidate gene sperm‐associated antigen 1 (SPAG1) [NC_049234.1:g.2213788_2213789insGGCGGCGGCAAGCGGCCGGAGAGGGGCGC] was identified as likely causative for PCD in this family. The 29 bp frameshift variant was unobserved in a public variant call file including 1987 dogs from the Dog10K resource however an in‐frame insertion was sometimes observed at the same locus. A Cocker Spaniel with similar symptoms from a different family tested negative for the identified variant suggesting that there are multiple causes for the condition in Cocker Spaniels.
S. E. Mead, L. Hambrook, R. Suryadinata et al.· Animal Genetics· 0 citations
Acephalic spermatozoa syndrome (ASS) is a rare cause of male infertility characterized by sperm tails lacking heads. Although zinc finger MYND-type containing 15 (ZMYND15) mutations are linked to male infertility, their role in ASS is unknown. In this study, whole-exome sequencing identified novel homozygous truncating mutations, c.292C>T (p.Arg98Ter) and c.337G>T (p.Glu113Ter), in ZMYND15 from two infertile patients. These mutations caused protein truncation and impaired function, leading to extremely low sperm counts, poor motility, and numerous acephalic spermatozoa. Electron microscopy and sperm immunofluorescence revealed abnormal sperm neck structures, missing mitochondrial sheaths, failure of acrosome formation, and a lack of central microtubules. Experiments showed reduced mutant protein expression and high rates of degradation. Coimmunoprecipitation experiments indicated a direct interaction between ZMYND15 and Sad1 and UNC84 domain containing 5 (SUN5), crucial for forming the sperm head-tail connection. One patient achieved a live birth via intracytoplasmic sperm injection (ICSI), whereas the other had an early miscarriage. This study links ZMYND15 mutations directly to ASS, highlighting its role in spermatogenesis and offering insights for clinical diagnosis and treatment.
Qian-Jun Zhang, Hao Lin, Rui-Long Hao et al.· Asian Journal of Andrology· 0 citations
This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies.
Yuting Lu, Hui-Yan Tang, Kai Chen et al.· Frontiers in Genetics· 0 citations