Female Infertility Caused by Mutations in the Oocyte-Specific Translational Repressor PATL2

Abstract

Infertility is a relatively common disorder of the reproductive system and remains unexplained in many cases. In vitro fertilization techniques have uncovered previously unrecognized infertility phenotypes, including oocyte maturation arrest, the molecular etiology of which remains largely unknown. We report two families affected by female-limited infertility caused by oocyte maturation failure. Positional mapping and whole-exome sequencing revealed two homozygous, likely deleterious variants in PATL2, each of which fully segregates with the phenotype within the respective family. PATL2 encodes a highly conserved oocyte-specific mRNP repressor of translation. Previous data have shown the strict requirement for PATL2 in oocyte-maturation in model organisms. Data gathered from the families in this study suggest that the role of PATL2 is conserved in humans and expand our knowledge of the factors that are necessary for female meiosis.

Keywords: GVBD; IVF; P100; PAT1A; maturation arrest; meiosis.

Figure 1

Identification of Individuals with a Phenotype Involving Oocyte Maturation Arrest (A and B) Images of an immature oocyte with a germinal vesicle (A, white circle) and a mature oocyte with a polar body (B, yellow circle) from a normal woman. (C–E) Images of immature oocytes from the individual with a maturation arrest phenotype from family 1. (C) An oocyte retrieved from a stimulated ovary. (D and E) Immature oocytes after 24 (D) and 48 (E) hr culture in in vitro maturation media indicate failure in maturation. Pedigrees of family 1 (F) and family 2 (G) are shown. WES was performed on the index individual (indicated by a red box) in each family.

Figure 2

Identification of PATL2 Variants in Individuals with a Phenotype Involving Oocyte Maturation Arrest (A) Shared haplotypes (chr15: 42,254,070–45,702,800; UCSC Genome Browser hg19) of the affected members from family 1 (IV:19 and IV:18) and family 2 (II:4 and II:5). Yellow lines indicate heterozygous SNPs. Red lines indicate rare homozygous SNPs. The lower panel shows genes that are within the shared ROH region. The position of PATL2 (chr15: 44,966,961–45,003,514; UCSC Genome Browser hg19) is highlighted with a red circle. (B) Genome-wide linkage analysis showing a chr15 peak with a pLOD score of 5.5 (16 individuals are included; see Figure S2 for details). (C) Genomic context and structural presentation of PTAL2, including the two variants. (D and E) The PAT1 domain contains the residues (Arg301, Leu302, Arg368, Ala327, Arg402, and Arg403) corresponding to the PATL1 residues involved in RNA binding (shown in dark blue). (D) Based on the structure of the corresponding region of PATL1 (PDB: 2XEQ; 34% sequence identity), the secondary-structure representation of the homology model of the C-terminal domain of PATL2 (residues 299–540) is shown. Gly370 is shown as orange spheres. (E) Magnified view of the outlined region in (D). In addition to Gly370 (orange), the putative p.Gly370Arg rotamer side chain (gray) with the least possible clashes (red discs) is shown, illustrating that p.Gly370Arg compromises the folding and function of PATL2.