Novel mutation in ODF2 causes multiple morphological abnormalities of the sperm flagella in an infertile male

Abstract

Numerous genes have been associated with multiple morphological abnormalities of the sperm flagella (MMAF), which cause severe asthenozoospermia and lead to male infertility, while the causes of approximately 50% of MMAF cases remain unclear. To reveal the genetic causes of MMAF in an infertile patient, whole-exome sequencing was performed to screen for pathogenic genes, and electron microscope was used to reveal the sperm flagellar ultrastructure. A novel heterozygous missense mutation in the outer dense fiber protein 2 ( ODF2 ) gene was detected, which was inherited from the patient's mother and predicted to be potentially damaging. Transmission electron microscopy revealed that the outer dense fibers were defective in the patient's sperm tail, which was similar to that of the reported heterozygous Odf2 mutation mouse. Immunostaining of ODF2 showed severe ODF2 expression defects in the patient's sperm. Therefore, it was concluded that the heterozygous mutation in ODF2 caused MMAF in this case. To evaluate the possibility of assisted reproductive technology (ART) treatment for this patient, intracytoplasmic sperm injection (ICSI) was performed, with the help of a hypo-osmotic swelling test and laser-assisted immotile sperm selection (LAISS) for available sperm screening, and artificial oocyte activation with ionomycin was applied to improve the fertilization rate. Four ICSI cycles were performed, and live birth was achieved in the LAISS-applied cycle, suggesting that LAISS would be valuable in ART treatment for MMAF.

Macrophage-Related Testicular Inflammation in Individuals with Idiopathic Non-Obstructive Azoospermia: A Single-Cell Analysis

“…Belonging to the outer dense fibers (ODFs) family, ODF2 is an accessory cytoskeletal structure that safeguards the sperm tail from shear forces [28,29]. It has been reported that patients with ODF2 deficiency and asthenozoospermia exhibit multiple abnormalities in sperm flagella morphology (MMAF) [30]. Based on our study, it seems that the decreased expression in the two genes is related to testicular inflammation and reduced spermatogenesis processes in iNOA patients, as the blue module had negative correlation with the turquoise.…”

Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse

“…Despite the number of proteins making up the centrosome, and its importance in sperm differentiation and flagellum formation, very few centrosomal proteins have been linked to MMAF in humans -so far only CEP135 [34], CEP148 [35] or DZIP1 [36]. Moreover, some major axonemal proteins with an accessory location in the centrosome, such as CFAP58 [37] and ODF2 [38,39], have also been reported to be involved in MMAF syndrome.…”

Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse

“…Despite the number of proteins making up the centrosome, and its importance in sperm differentiation and flagellum formation, very few centrosomal proteins have been linked to MMAF in humans – so far only CEP135 [34], CEP148 [35] or DZIP1 [36]. Moreover, some major axonemal proteins with an accessory location in the centrosome, such as CFAP58 [37] and ODF2 [38, 39], have also been reported to be involved in MMAF syndrome. Other centrosomal proteins lead to MMAF in mice, these include CEP131 [40] and CCDC42 [41].…”