DPY19L2 Deletion as a Major Cause of Globozoospermia

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DPY19L2 Deletion as a Major Cause of Globozoospermia Isabelle Koscinski, Elias ElInati, Camille Fossard, Claire Redin, Jean Muller, Juan Velez de la Calle, Françoise Schmitt, Mariem Ben Khelifa, Pierre Ray, Zaid Kilani, Christopher L.R. Barratt, Stéphane Viville The American Journal of Human Genetics Volume 88, Issue 3, Pages 344-350 (March 2011) DOI: 10.1016/j.ajhg.2011.01.018 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and Linkage Analysis of the Jordanian Family (A) Jordanian pedigree showing second-degree consanguinity. (B) SNP array results of the four infertile and three fertile brothers for the region of chromosome12. Shared regions of homozygosity are visualized by the HomoSNP software, which displays one patient per line. The areas of homozygosity with 25 or more SNPs are black, whereas homozygosity regions defined by 15–25 consecutive SNPs are gray. Regions of heterozygosity are light gray. The four affected siblings, Globo1 to Globo4 (IV-1 to IV-4), share a region of homozygosity of 6.4 Mb on chromosome 12, which is not shared by the three fertile brothers, B1 to B3 (IV-5 to IV-7). The American Journal of Human Genetics 2011 88, 344-350DOI: (10.1016/j.ajhg.2011.01.018) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Analysis of DPY19L2 (A) Schematic representation of DPY19L2 flanked by two LCRs, LCR1 and LCR2. LCR1 is located upstream of the gene and LCR2 downstream. Different sequences were amplified on both sides of the gene in order to determine the breakpoints: “a,” “b,” and “c” sequences are localized in LCR1, whereas “d” and “e” sequences are localized in LCR2. Mismatches between the two LCRs sequences are represented by (∗) in the 5′ side and by (.) in the 3′ side. (B) PCR results of DPY19L2 exons and flanking regions. Patients Globo1, Globo7, Globo17, and Globo18 are deleted for exons 2, 7, 9, 10, 13, 17, and 21, whereas the positive control showed an amplification of all of these exons. All patients showed specific amplifications for region “a” in LCR1 and region “e” in LCR2. Globo1 and Globo18 are missing region “b” in LCR1, which is not the case for Globo7 and Globo17. Globo7 is the only patient missing region “d” in LCR2. A DNA ladder was included on both sides of each gel for accurate determination of the PCR band size. (C) PCR of DPY19L2 breakpoints. This PCR was performed with the use of the “LCR1a forward” and “DPY19L2-BP reverse” primers (Table S4). The four globozoospermic patients showed a fragment of 1700 bp. The fertile brother (B1, IV-5 in Figure 1A) is homozygous wild-type, because no fragment was amplified, whereas parents of Globo18 (P1 and P2) and Globo17 (P3 and P4) are heterozygous. A fertile man (positive control) was used as control of the PCR specificity. Amplification of exon 10 (lower panel) was used to control the presence or absence of DPY19L2. (D) Table summarizing the PCR results of the four patients: (+) indicates presence of a PCR band at the corresponding size, and (-) indicates absence of a PCR band. (E) Schematic representation of the breakpoint area determined for Globo1, Globo18, and the paternal allele of Globo17. The breakpoint area (DPY19L2-BP1) identified by PCR and sequencing is defined between the two discontinued lines and represented by a hatched box in the recombined LCR. (F) Schematic representation of the homologous recombination that occurred in Globo7 and the maternal allele of Globo17. The breakpoint area (DPY19L2-BP2) identified by PCR and sequencing is defined between the two discontinued lines and represented by a hatched box in the recombined LCR. The American Journal of Human Genetics 2011 88, 344-350DOI: (10.1016/j.ajhg.2011.01.018) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 CNVs at the DPY19L2 Locus CNVs are displayed as rectangles according to the following scheme: gains are drawn with hatched lines, losses with plain rectangles, and vertical lines are used when both gains and losses are observed. The CNVs excluded from the count are colored in gray. LCR1 and LCR2 are displayed as dark gray rectangles on top of the gene representation. The American Journal of Human Genetics 2011 88, 344-350DOI: (10.1016/j.ajhg.2011.01.018) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Seminal Germ Cells in Patients with DPY19L2 Deletion (A) Detailed seminal germ cell of Globo7. There is no evidence of defective spermatogenesis in immature germ cells; the spermatid polarization and elongation is consistent with controls: e.g., the correct positioning of the chromatid body (blue arrows), except for the absence of the acrosomal vesicle. (B) Spermatozoa and spermatids of fertile controls. The acrosome is clearly observed in spermatozoa and elongating spermatid (arrows). (C–E) Spermatozoa and spermatid of Globo17, Globo18, and Globo7, respectively. The spermatozoa present the typical round head and an absence of acrosome. No evident polarization abnormality in seminal spermatids was observed in the globozoospermic patients. The American Journal of Human Genetics 2011 88, 344-350DOI: (10.1016/j.ajhg.2011.01.018) Copyright © 2011 The American Society of Human Genetics Terms and Conditions