Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,

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Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Xueqian Wang, Zheng Yan, Bin Li, Yao Xu, Min Yu, Jing Fu, Jian Mu, Zhou Zhou, Qiaoli Li, Li Jin, Lin He, Qing Sang, Lei Wang The American Journal of Human Genetics Volume 101, Issue 4, Pages 609-615 (October 2017) DOI: 10.1016/j.ajhg.2017.08.018 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Mutations in PATL2 (A) Five pedigrees affected by oocyte maturation arrest. All five affected individuals have biallelic mutations with a recessive inheritance pattern. The proband from family 1 (with consanguineous parents) has a homozygous nonsense mutation in PATL2. The other individuals from families 2–5 carry compound-heterozygous variants derived from both parents. Sanger sequencing confirmation is shown below the pedigrees. Equal signs indicate infertility, and the double line between individuals I-1 and I-2 in family 1 indicates consanguinity. Black circles represent the proband. In family 2, the sister of the affected individual carrying a heterozygous mutation was not married, and her fertility was unknown. (B) Homozygosity mapping of individual II-1 in family 1. Homozygous regions harboring the strongest signal are indicated in red. The asterisk indicates the area where PATL2 is located. (C) Locations and conservation of mutations in PATL2. The positions of all mutations are indicated in the genomic structure of PATL2. The affected amino acids were compared among six mammalian species in a conservation analysis. The American Journal of Human Genetics 2017 101, 609-615DOI: (10.1016/j.ajhg.2017.08.018) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Phenotypes of Oocytes Retrieved from Affected Individuals (A) The morphology of normal and affected individuals’ germinal vesicle (GV), metaphase I (MI), and first polar body (PB1) oocytes. Individuals from families 3 and 4 had some PB1 oocytes, but these had abnormal PB1s, as indicated by the arrows. The scale bar represents 50 μm. (B) Immunolabeling of normal and affected individuals’ oocytes at different stages. Oocytes were immunolabeled with antibodies against PATL2 (shown in green) for visualization of the protein distribution and were counterstained with Hoechst 33342 (shown in blue) for DNA visualization. The morphologies of the oocytes were examined with an inverted microscope system (OLYMPUS IX71), and the immunolabeling was examined by confocal microscopy (Leica). PATL2 was mostly located in the cytoplasm of normal oocytes and gradually degraded during oocyte maturation. The affected individuals’ oocytes showed lower fluorescence than the normal oocytes, implying that the amount of PATL2 was greatly impaired by these mutations. The scale bar represents 50 μm. The American Journal of Human Genetics 2017 101, 609-615DOI: (10.1016/j.ajhg.2017.08.018) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 A Schematic Representation of the PATL2 Splice Aberrations That Lead to Protein Truncation in Affected Individuals (A) Schematic illustrating the effect of the PATL2 c.223−14_223−2del CCCTCCTGTTCCA splice-site mutation. The acceptor −2A deletion disrupted the canonical acceptor splicing site and resulted in an alternative acceptor ahead of the site, causing a 49-bp insertion between exons 3 and 4. (B) Schematic illustrating the effect of the PATL2 c.1224+2T>C splice-site mutation. The donor +2T>C mutation missed the canonical donor splice site and made the next downstream splice site the donor site, causing a 43-bp insertion between exon 12 and exon 13 (transcript variant 1) or exon 14 (transcript variant 2). Both types of splicing mutations resulted in premature termination. The American Journal of Human Genetics 2017 101, 609-615DOI: (10.1016/j.ajhg.2017.08.018) Copyright © 2017 American Society of Human Genetics Terms and Conditions