Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive...

Area of Science:

• Genetics
• Reproductive Biology
• Male Infertility

Background:

• Non-obstructive azoospermia (NOA) is a significant cause of male infertility.
• The genetic basis of NOA is not fully understood, particularly congenital factors.

Purpose of the Study:

• Identify and characterize novel genetic variants linked to NOA.
• Focus on the TEX14 gene's role in intercellular bridge (ICB) formation during meiosis.

Main Methods:

• Exome sequencing of 673 NOA patients, 143 oligozoospermia individuals, and 100 controls.
• Identification and Sanger sequencing confirmation of TEX14 variants.
• Functional analysis (qPCR, Western blot, mouse models) of TEX14 expression and its impact on spermatogenesis and ICB formation.

Main Results:

• Six novel TEX14 variants (frameshift, missense, splicing) identified in four infertile men.
• A mouse model with a TEX14 frameshift mutation (Tex14MT1/MT1) exhibited NOA phenotype with absent ICBs and meiotic arrest at the zygotene stage.
• Patient and mouse studies confirmed TEX14's essential role in ICB formation and meiotic progression.

Conclusions:

• Loss-of-function TEX14 mutations disrupt ICB formation, causing zygotene arrest and NOA in humans and mice.
• Expands the known genetic variants associated with NOA.
• Establishes TEX14's critical role in male fertility and meiotic progression.