A homozygous TRIP13 pathogenic variant associated with familiar oocyte arrest and prematurely condensed sperm chromosomes.

Abstract

We report on a consanguineous family with two infertile sisters with oocyte arrest and prematurely condensed sperm chromosomes. A genome-wide linkage scan and exome sequencing revealed a homozygous variant in the gene for the thyroid receptor interacting protein 13 (TRIP13), c.518G˃A (p.Arg173Gln), affecting an evolutionary highly conserved amino acid within an ATP binding motif. Just recently, compound heterozygosity for this variant was described in a Chinese proband as pathogenic, confirming that the homozygous mutation is causative for the oocyte arrest. The TRIP13 gene and the orthologous yeast pch2 gene are, amongst others, involved in a meiotic checkpoint control. This checkpoint defect is obviously responsible for the premature condensation of the sperm chromosomes. TRIP13 and pch2 are involved in meiotic recombination. To exclude that it is involved in reciprocal somatic exchanges, we analyzed the rate of sister chromatid exchanges (SCEs) in the proband´s lymphoblastoid cells. Obviously, TRIP13 is not involved in this type of somatic recombination. Moreover, we tested whether TRIP13 can complement the defect of the yeast pch2 gene. Using a yeast deletion strain lacking pch2, we integrated plasmids containing either the yeast pch2 or the human TRIP13 gene, both harboring the wild-type or the mutant allele and assessed the crossingover rate between marker genes lys2 and leu2 as a measure of complementation. Evidence is presented that the human plasmids, unexpectedly also that with the mutation, could complement the pch2 deficient yeast strain, underlining that the evolutionary conservation at the molecular level obviously extends to the functional level.