Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome Fuxi Zhu, Fengsong Wang, Xiaoyu Yang, Jingjing Zhang, Huan Wu, Zhou.

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Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome Fuxi Zhu, Fengsong Wang, Xiaoyu Yang, Jingjing Zhang, Huan Wu, Zhou Zhang, Zhiguo Zhang, Xiaojin He, Ping Zhou, Zhaolian Wei, Jozef Gecz, Yunxia Cao The American Journal of Human Genetics Volume 99, Issue 4, Pages 942-949 (October 2016) DOI: 10.1016/j.ajhg.2016.08.004 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Analysis of the Sperm of Infertile Men with Acephalic Spermatozoa Syndrome Due to Mutations in SUN5 (A and B) Photomicrographs of ejaculated semen smear stained by Papanicolaou. The majority of the ejaculated spermatozoa are headless (white arrowhead). A small proportion of intact spermatozoa have an abnormal head-tail junction (red arrow), and a few tailless heads (white arrow) can be observed. (C–F) Transmission electron micrographs of the representative spermatozoa. A headless spermatozoon contains the proximal centriole, segmented columns, mitochondria, and all the other components normally included in the tail (C). A tailless spermatozoon contains a slightly enlarged nucleus without a typical acrosome structure but lacks the implantation fossa and basal plate (D). A longitudinal section (E) and a cross section (F) of a spermatozoon with an abnormal head-tail junction show that the head is laterally inserted into the cytoplasmic residual body of the proximal tail. The head contains the nucleus and almost normally shaped acrosome but lacks the implantation fossa and basal plate at the caudal pole of the nucleus. The tail contains the proximal centriole, segmented columns, mitochondria (showed in C), and normally arranged axoneme (showed in C and E). The American Journal of Human Genetics 2016 99, 942-949DOI: (10.1016/j.ajhg.2016.08.004) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees and SUN5 Mutations in Families Affected by Acephalic Spermatozoa Syndrome (A) Pedigrees of the eight families with inherited SUN5 mutations are shown. The individuals with a single star were Sanger sequenced. Individuals F1:II-3 and F2:II-4 were tested by WES (two stars). (B) The domain architecture of SUN5 and the location of the SUN5 variants. The protein has 379 amino acids (gray) and contains a single transmembrane (TM) domain (green), a coiled-coil (CC) domain (blue), and a SUN domain (yellow). SUN5 is located on the inner nuclear membrane; the N terminus is in the nuclear space (light-blue background), and the C terminus extends to the perinuclear space (light-green background). (C) Western blot showing Lamin A/C (Proteintech antibodies, 10298-1-AP) and SUN5 (Proteintech antibodies, 17495-1-AP) levels on ejaculated sperm from two control individuals and four affected individuals with SUN5 variants. Molecular weights, showed in the left lane, were determined according to the protein molecular weight marker (Takara, broad range, 3452Q). (D) Agarose gel image of cDNA PCR products encompassing exons 10–13 of SUN5 (forward primer 5′-CCTGAAGTCTATAGGGGCCA-3′; reverse primer 5′-ATCTCTCTTAGGGTAGGGGTTC-3′). A single band of expected size was detected in individual F1:II-3, with the c.824C>T (p.Thr275Met) mutation, suggesting that this variant does not affect splicing. WT testis is a sample from an individual with prostate cancer who underwent bilateral castration treatment. NTC represents negative control. The American Journal of Human Genetics 2016 99, 942-949DOI: (10.1016/j.ajhg.2016.08.004) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 The Consequences of SUN5 Mutations on Protein Distribution in Sperm SUN5 immunofluorescence in sperm from control (WT) and affected individuals. SUN5 staining is confined to the head-tail junction region (exactly in the distal part of the inner nuclear membrane, which is close to the distal end of the nucleus) in control sperm (highlighted by white arrow). This specific pattern of distribution is not observed in abnormal head-tail junction spermatozoon of affected individuals with SUN5 mutations. Anti-α-tubulin antibody staining paints the tails of the sperm, and DAPI indicates the nucleus in the sperm head. The scale is shown at the bottom left panel. (Inset) Digital enlargement of the respective sperm head-tail junction regions. The American Journal of Human Genetics 2016 99, 942-949DOI: (10.1016/j.ajhg.2016.08.004) Copyright © 2016 American Society of Human Genetics Terms and Conditions