A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family Ying Ma, Ph.D., Ning Xie,

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A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family Ying Ma, Ph.D., Ning Xie, M.D., Dingxiong Xie, M.D., Litao Sun, Ph.D., Shuyan Li, Ph.D., Peiqiang Li, Ph.D., Yi Li, Ph.D., Jin Li, Ph.D., Zhilong Dong, Ph.D., Xiaodong Xie, Ph.D. Fertility and Sterility Volume 111, Issue 5, Pages 909-917.e1 (May 2019) DOI: 10.1016/j.fertnstert.2019.01.007 Copyright © 2019 The Authors Terms and Conditions

Figure 1 FBXO43 mutation in brothers with male infertility. (A) Pedigrees affected by male infertility. The affected family members (proband and his brother) are indicated as black squares. The proband (II.1) is indicated with an arrow. The genotypes for the mutation c.C1991T in gene FBXO43 are shown below the symbols. (B) Sanger sequencing confirmation of FBXO43 mutation, c. C1991T. The proband and his brother carried the homozygous mutation. His father and mother harbored the heterozygous allele. The arrow indicates the c. C1991T site. (C–G) Analysis of sperm morphology. (C, D, E) Normal spermatozoa from fertile control. (F, G, H) Spermatozoa from the proband. (F) The majority of the ejaculated spermatozoa presented with morphological abnormalities of the sperm head and neck, such as amorphous head (white arrowhead), vacuoles (orange arrow), and cytoplasm (cytoplasmic droplet or excess residual cytoplasm) (blue arrow). (G, H) Spermatozoa with disorganization in the heads. (G) Amorphous head with nucleus vacuoles (white arrowhead). (H) Amorphous head with excess residual cytoplasm (white arrow). Fertility and Sterility 2019 111, 909-917.e1DOI: (10.1016/j.fertnstert.2019.01.007) Copyright © 2019 The Authors Terms and Conditions

Figure 2 Positions and conservation of mutations in FBXO43 (II1, II2, and P1–P4). Homozygous mutation is colored red (II1, II2), and heterozygous mutations are colored grey (P1–P4). (A) The FBXO43 gene includes five exons. The positions of five point mutations in the FBXO43 gene are shown. (B) The FBXO43 protein includes an F-box and the zinc-binding region (ZBR) in the C terminus. The positions of the five affected amino acid residues in FBXO43 protein are shown. (C) The conservation of the five mutations was analyzed across different species. Fertility and Sterility 2019 111, 909-917.e1DOI: (10.1016/j.fertnstert.2019.01.007) Copyright © 2019 The Authors Terms and Conditions

Figure 3 Structural model of FBXO43 protein with the G664D mutation. (A, B) Three-dimensional model, presented as cartoon. (A) Wild type. (B) Mutation G664D. (C) Three structural changes in G664D mutation compared with wild type: Ⅰ, the changes in the loops; Ⅱ, an additional α-helix; Ⅲ, two short β-sheets. (D) Magnified view of the outlined region highlighting the change of mutant residue G664D and the surrounding β-sheet. Fertility and Sterility 2019 111, 909-917.e1DOI: (10.1016/j.fertnstert.2019.01.007) Copyright © 2019 The Authors Terms and Conditions

Supplemental Figure 1 Analysis of the sperm of sporadic patients harboring mutations of FBXO43 gene (P1–P4). Photomicrographs of ejaculated semen smear with Papanicolaou stain. The majority of the ejaculated spermatozoa presented with amorphous head, vacuoles, cytoplasmic droplet, and/or excess residual cytoplasm. Fertility and Sterility 2019 111, 909-917.e1DOI: (10.1016/j.fertnstert.2019.01.007) Copyright © 2019 The Authors Terms and Conditions