Loss‐of‐function mutation in <i>TSGA10</i> causes acephalic spermatozoa phenotype in human

Ye, Yuanyuan; Wei, Xiaoli; Sha, Yanwei; Li, Na; Yan, Xiaohong; Cheng, Lin; Qiao, Duanrui; Zhou, Weidong; Wu, Rong‐Feng; Liu, Qiaobin; Li, Youzhu

doi:10.1002/mgg3.1284

Cited by 25 publications

(23 citation statements)

References 22 publications

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“…In addition, it has only been reported in the gnomAD database in the heterozygous state and with an allelic frequency (AF) of 0.0166%. In the two remaining patients, we did not identify any bi-allelic deleterious variant in potential candidate genes, which were defined as follows: (1) other genes involved in acephalic spermatozoa syndrome, particularly in PMFBP1 and TSGA10 [ 17 , 18 , 19 , 20 ]; (2) genes previously described in a context of male infertility; or (3) genes with a predominant testicular expression or restricted expression in the testes.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa

Cazin

Boumerdassi

Martinez

et al. 2021

IJMS

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Acephalic spermatozoa syndrome (ASS) is a rare but extremely severe type of teratozoospermia, defined by the presence of a majority of headless flagella and a minority of tail-less sperm heads in the ejaculate. Like the other severe monomorphic teratozoospermias, ASS has a strong genetic basis and is most often caused by bi-allelic variants in SUN5 (Sad1 and UNC84 domain-containing 5). Using whole exome sequencing (WES), we investigated a cohort of nine infertile subjects displaying ASS. These subjects were recruited in three centers located in France and Tunisia, but all originated from North Africa. Sperm from subjects carrying candidate genetic variants were subjected to immunofluorescence analysis and transmission electron microscopy. Moreover, fluorescent in situ hybridization (FISH) was performed on sperm nuclei to assess their chromosomal content. Variant filtering permitted us to identify the same SUN5 homozygous frameshift variant (c.211+1_211+2dup) in 7/9 individuals (78%). SUN5 encodes a protein localized on the posterior part of the nuclear envelope that is necessary for the attachment of the tail to the sperm head. Immunofluorescence assays performed on sperm cells from three mutated subjects revealed a total absence of SUN5, thus demonstrating the deleterious impact of the identified variant on protein expression. Transmission electron microscopy showed a conserved flagellar structure and a slightly decondensed chromatin. FISH did not highlight a higher rate of chromosome aneuploidy in spermatozoa from SUN5 patients compared to controls, indicating that intra-cytoplasmic sperm injection (ICSI) can be proposed for patients carrying the c.211+1_211+2dup variant. These results suggest that the identified SUN5 variant is the main cause of ASS in the North African population. Consequently, a simple and inexpensive genotyping of the 211+1_211+2dup variant could be beneficial for affected men of North African origin before resorting to more exhaustive genetic analyses.

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Section: Resultsmentioning

confidence: 99%

Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa

Cazin

Boumerdassi

Martinez

et al. 2021

IJMS

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“…A Crispr/Cas-mediated depletion of TSGA10, a mitochondrial-associated protein, causes infertility in heterozygous male mice, with reduced sperm count and disordered mitochondrial sheath formation. Infertile patients suffering from ASS have revealed mutations in TSGA10 by whole-exome sequencing [ 156 , 157 , 183 , 184 ]. TSGA10 has been identified as a centrosomal and basal body protein that interacts with ODF2 [ 185 ].…”

Section: The Protein Components Of the Connecting Piece And Their Relevance For The Head-to-tail Linkage And Male Fertilitymentioning

confidence: 99%

The Transformation of the Centrosome into the Basal Body: Similarities and Dissimilarities between Somatic and Male Germ Cells and Their Relevance for Male Fertility

Contreras¹,

Hoyer‐Fender²

2021

Cells

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The sperm flagellum is essential for the transport of the genetic material toward the oocyte and thus the transmission of the genetic information to the next generation. During the haploid phase of spermatogenesis, i.e., spermiogenesis, a morphological and molecular restructuring of the male germ cell, the round spermatid, takes place that includes the silencing and compaction of the nucleus, the formation of the acrosomal vesicle from the Golgi apparatus, the formation of the sperm tail, and, finally, the shedding of excessive cytoplasm. Sperm tail formation starts in the round spermatid stage when the pair of centrioles moves toward the posterior pole of the nucleus. The sperm tail, eventually, becomes located opposed to the acrosomal vesicle, which develops at the anterior pole of the nucleus. The centriole pair tightly attaches to the nucleus, forming a nuclear membrane indentation. An articular structure is formed around the centriole pair known as the connecting piece, situated in the neck region and linking the sperm head to the tail, also named the head-to-tail coupling apparatus or, in short, HTCA. Finally, the sperm tail grows out from the distal centriole that is now transformed into the basal body of the flagellum. However, a centriole pair is found in nearly all cells of the body. In somatic cells, it accumulates a large mass of proteins, the pericentriolar material (PCM), that together constitute the centrosome, which is the main microtubule-organizing center of the cell, essential not only for the structuring of the cytoskeleton and the overall cellular organization but also for mitotic spindle formation and chromosome segregation. However, in post-mitotic (G1 or G0) cells, the centrosome is transformed into the basal body. In this case, one of the centrioles, which is always the oldest or mother centriole, grows the axoneme of a cilium. Most cells of the body carry a single cilium known as the primary cilium that serves as an antenna sensing the cell’s environment. Besides, specialized cells develop multiple motile cilia differing in substructure from the immotile primary cilia that are essential in moving fluids or cargos over the cellular surface. Impairment of cilia formation causes numerous severe syndromes that are collectively subsumed as ciliopathies. This comparative overview serves to illustrate the molecular mechanisms of basal body formation, their similarities, and dissimilarities, in somatic versus male germ cells, by discussing the involved proteins/genes and their expression, localization, and function. The review, thus, aimed to provide a deeper knowledge of the molecular players that is essential for the expansion of clinical diagnostics and treatment of male fertility disorders.

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“…Acephalic spermatozoa (AS) syndrome is a rare form of teratozoospermia. Only a few genetic alteration studies have been reported, and these studies found that variants in SUN5 , 1,2 PMFBP1 , 3,4 TSGA10 , 5–7 BRDT , 8 SPATC1L , 9 and HOOK1 10 are associated with this phenotype. Furthermore, most AS cases are idiopathic.…”

Section: Introductionmentioning

confidence: 99%

Patients with acephalic spermatozoa syndrome linked to novel TSGA10/PMFBP1 variants have favorable pregnancy outcomes from intracytoplasmic sperm injection

et al. 2021

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Acephalic spermatozoa syndrome is a rare form of teratozoospermia characterized by headless spermatozoa. Previous studies have found that variants in SUN5, PMFBP1, TSGA10, BRDT, and SPATC1L are associated with this phenotype. Many researchers have suggested that variants in TSGA10 without a proximal centriole might influence early embryonic development. This retrospective cohort study included 12 infertile men with severe acephalic spermatozoa in China. We identified six heterozygous variants and four homozygous variants in TSGA10/PMFBP1 in seven patients by whole‐exome sequencing (WES). Acephalic spermatozoa defects due to different genetic variations may affect only spermatozoa morphology but do not reduce the chances of fertilization, affect embryo quality at early stages or impair intracytoplasmic sperm injection (ICSI) outcomes. Patients with TSGA10/PMFBP1 variations were all expected to have good prognoses with ICSI.

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Loss‐of‐function mutation in TSGA10 causes acephalic spermatozoa phenotype in human

Cited by 25 publications

References 22 publications

Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa

Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa

The Transformation of the Centrosome into the Basal Body: Similarities and Dissimilarities between Somatic and Male Germ Cells and Their Relevance for Male Fertility

Patients with acephalic spermatozoa syndrome linked to novel TSGA10/PMFBP1 variants have favorable pregnancy outcomes from intracytoplasmic sperm injection

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