Biallelic mutations in PMFBP1 cause acephalic spermatozoa

Abstract

The majority of men with defects in spermatogenesis remain undiagnosed. Acephalic spermatozoa is one of the diseases causing primary infertility. However, the causes underlying over half of affected cases remain unclear. Here, we report by whole‐exome sequencing the identification of homozygous and compound heterozygous truncating mutations in PMFBP1 of two unrelated individuals with acephalic spermatozoa. PMFBP1 was highly and specifically expressed in human and mouse testis. Furthermore, immunofluorescence staining in sperm from a normal control showed that PMFBP1 localizes to the head‐flagella junction region, and the absence of PMFBP1 was confirmed in patients harboring PMFBP1 mutations. In addition, we generated Pmfbp1 knock‐out (KO) mice, which we found recapitulate the acephalic sperm phenotype. Label‐free quantitative proteomic analysis of testicular sperm from Pmfbp1 KO and control mice showed 124 and 35 proteins, respectively, increased or decreased in sperm from KO mice compared to that found in control mice. Gene ontology analysis indicates that the biological process of Golgi vesicle transport was the most highly enriched in differentially expressed proteins, indicating process defects related to Golgi complex function may disturb formation of the head‐neck junction. Collectively, our data indicate that PMFBP1 is necessary for sperm morphology in both humans and mice, and that biallelic truncating mutations in PMFBP1 cause acephalic spermatozoa.

Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes

“…Based on ultrastructural observations and genetic variations, the broken points of sperm necks are AS defects that can be classified into three subtypes (shown in Table 1): I, II, and III. e differences in AS phenotypes between subtypes strongly highlight the genetic variations found in AS defects, which have been reported in both animal and human studies [4,10,11,27].…”

“…e ratio of headless to tailless sperm in semen is over 30 : 1 [7] since most of the heads are phagocytosed by Sertoli cells [4,8,9]. e aetiology and pathogenesis of AS affected individuals have been shown to be genetic in origin, with five identified AS genes [10][11][12]: SUN5, BRDT, PMFBP1, TSGA10, and HOOK1. e natural fertilising abilities of these genes are lost because almost all AS sperm are broken in two.…”

“…Intracytoplasmic sperm injection (ICSI) is the only technique so far in which abnormal or immotile sperm have the opportunity to fertilise oocytes successfully [13,14]. Meanwhile, Sha et al [11] believed that ICSI was the only solution to AS defects; however, not all AS-deficient sperm achieved the same clinical results [15].…”

Loss‐of‐function mutations in centrosomal protein 112 is associated with human acephalic spermatozoa phenotype

“…The screening criteria for the acephalic spermatozoa were the same as previously published. 13,17,23…”

Novel mutations in PMFBP1, TSGA10 and SUN5: Expanding the spectrum of mutations that may cause acephalic spermatozoa

“…PMFBP1 interacts with SUN5 2 but does not directly bind to SUN5 or SPATA6, 2 and PMFBP1 and TSGA10 have the same Smc superfamily domain. They may associate with the centrosome and basal body and participate in completing the coupling apparatus, ultimately resulting in acephalic spermatozoa [2][3][4] but not delayed or stagnated embryonic development.…”