Molecular Analysis of DPY19L2, PICK1 and SPATA16 in Italian Unrelated Globozoospermic Men

Abstract

This study aims to evaluate genetic contribution and sperm DNA fragmentation (SDF) in a cohort of 18 unrelated globozoospermic Italian men (Group G). Semen samples were assessed according to the WHO 2010 Laboratory Manual and compared with 31 fertile controls. We focused our genetic analysis on the exons of the main globozoospermia-associated genes, performing qualitative PCR to assess deletion of DPY19L2 and sequencing to detect mutations of SPATA16 and PICK1. SDF was evaluated using the TUNEL assay. In Group G, 10 patients had a complete form of globozoospermia, whereas 8 patients had a partial form. Molecular analysis revealed deletion of DPY19L2 in six of the patients, all of them with complete globozoospermia, while no mutations were found in the examined exons of PICK1 and SPATA16. TUNEL analysis showed a higher SDF% in Group G. Our findings confirm DPY19L2 defects as the most frequent genetic alteration in Italian patients contributing to globozoospermic phenotypes. Furthermore, spermatozoa with acrosomal defects could also display high levels of SDF as a possible consequence of abnormally remodeled chromatin. The possible effect on offspring of chromatin structure abnormalities and altered DNA integrity should be carefully evaluated by clinicians, especially regarding the feasibility and safety of artificial reproductive techniques, which represent the only treatment that allows these patients to conceive.

Globozoospermia: A Case Report and Systematic Review of Literature

“…Finally, 86 articles met our inclusion criteria and, therefore, were included in this systematic review ( Fig. 2 ) [ 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106…”

“…A total of 49 articles evaluated the prevalence and type of genetic abnormalities present in patients with globozoospermia [ 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 ] ( Table 3 ). The gene more frequently involved in the pathogenesis of globozoospermia is DPY19L2 and the mutation most frequently described is the deletion of the entire gene that, which has been reported to have a prevalence ranging from 22.2% [ 98 ] to 83.3% [ 105 ].…”

“…Among other mutations of DPY19L2 associated with globozoospermia, homozygous or compound heterozygous deletions of some exons have been reported. These include the involvement of exons 5, 6, 7, 10, 11, 12, and 22 [ 29 36 37 45 98 106 ]. In other cases, point mutations or few nucleotide deletions in both homozygosity and compound heterozygosity, together with other point mutations or deletions of the DPY19L2 gene have been described [ 31 33 35 38 52 58 104 109 ].…”

“…Fourty-eight articles evaluated the genetic background of patients with globozoospermia [ 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 ]. Among these, we searched for the rate of sperm aneuploidies to assess the possible risk of transmission of genetic abnormalities to offspring ( Table 3 ).…”

Human globozoospermia‐related genes and their role in acrosome biogenesis

“…Since Pick1 is a soluble peripheral protein, it is possible to propose that it is present at the outer acrosomal membrane during spermiogenesis and in mature spermatozoa (Cao et al, 2007). However, recent studies have failed to find the PICK1 mutation in infertile patients with globozoospermia (Faja et al, 2021; Modarres et al, 2016; Oud et al, 2020). The real contribution of this gene in the origin of globozoospermia remains undetermined.…”