Observational Study

Authors: Yi Zhang, Peng Zhan, Yanli Wang...

Asthenozoospermia (AZS) is the commonest cause of male-related infertility. The patients with AZS easily exhibit infertility, with their wives having spontaneous miscarriages or seeking assisted reproductive treatment. Reciprocal chromosomal translocation (RCT) is an important chromosome structural abnormality and has been reported to affect sperm motility. Genetic counseling for male RCT patients with AZS is still a challenge. This study reported 4 RCT carriers, which were 46,XY,t(1;6) (p36.1;p21), 46,XY,t (6;10) (p21;q11.2), 46,XY,t (6;11) (p21;p15), and 46,XY,t (6;17) (p21;q21), respectively. The association between chromosome 6p21 translocation and AZS is discussed, considering 19 published cases as well. In 6 patients with available semen parameters and 4 patients in this study, all of them were diagnosed with AZS. The SLC26A8 gene and the DNAH8 gene located on chromosome 6p21 are closely related to AZS by gene search using OMIM. For the chromosome 6p21 breakpoint, 72 pathogenic genes were found through the DECIPHER search. Gene ontology analysis showed that these target genes have several molecular functions and are strongly involved in various biological processes. The proteins expressed by these genes are involved in multiple cellular components. These results suggest that the breakpoint of chromosome 6p21 in male RCT carriers is closely related to AZS. The breakpoint may disrupt the structure and function of related genes, resulting in reduced sperm motility. Karyotype analysis should be recommended for AZS patients. Chromosomes and breakpoints involved in RCT should be paid attention to in genetic counseling for patients.

Topics: Male; Humans; Asthenozoospermia; Translocation, Genetic; Infertility, Male; Chromosome Aberrations; Karyotype

PubMed: 37417617
DOI: 10.1097/MD.0000000000034318

Authors: Peng Zhan, Tingting Hao, Xiao Yang...

Chromosomal aberrations in peripheral blood are a major cause of reproductive disorders for the infertile couples. Reciprocal translocation is closely related to male infertility. The breakpoint of translocation may disrupt or dysregulate important genes related to spermatogenesis. The relationship between some breakpoints of chromosome and male infertility has been paid attention. Chromosome 22q11.2 translocation has not been reported with male infertility. The purpose of this study is to evaluate the relationship between chromosome 22q11.2 translocation and male infertility. All patients were collected from the second hospital of Jilin University. Semen parameters were detected using the computer-aided semen analysis system. Cytogenetic analysis was performed using standard operating procedure. Related genes on chromosomal breakpoints were searched using online mendelian inheritance in man (OMIM). The association between this breakpoint and spermatogenesis is also discussed. We report 6 cases of translocation in chromosome 22. Of 7 breakpoints involved in these translocations, the common feature is that they all included chromosome 22q11.2 translocation and presented with oligozoospermia. The analysis of breakpoint related genes showed testis-specific serine/threonine kinase 2 (TSSK2) gene is associated with human spermatogenesis impairment. Overall, these results suggest that the breakpoint involved in translocation deserves attention from physicians in genetic counseling. The breakpoint rearrangement has the possibility of disrupting spermatogenesis. The relationship between 22q11.2 breakpoint and male infertility deserves further study.

Topics: Chromosome Aberrations; Chromosomes; Humans; Infertility, Male; Male; Oligospermia; Protein Serine-Threonine Kinases; Serine; Translocation, Genetic

PubMed: 36181097
DOI: 10.1097/MD.0000000000030790

Authors: Hitomaru Miyamoto, Hiroaki Kobayashi, Nanami Kishima...

A 'genomically' humanized animal stably maintains and functionally expresses the genes on human chromosome fragment (hCF; <24 Mb) loaded onto mouse artificial chromosome (MAC); however, cloning of hCF onto the MAC (hCF-MAC) requires a complex process that involves multiple steps of chromosome engineering through various cells via chromosome transfer and Cre-loxP chromosome translocation. Here, we aimed to develop a strategy to rapidly construct the hCF-MAC by employing three alternative techniques: (i) application of human induced pluripotent stem cells (hiPSCs) as chromosome donors for microcell-mediated chromosome transfer (MMCT), (ii) combination of paclitaxel (PTX) and reversine (Rev) as micronucleation inducers and (iii) CRISPR/Cas9 genome editing for site-specific translocations. We achieved a direct transfer of human chromosome 6 or 21 as a model from hiPSCs as alternative human chromosome donors into CHO cells containing MAC. MMCT was performed with less toxicity through induction of micronucleation by PTX and Rev. Furthermore, chromosome translocation was induced by simultaneous cleavage between human chromosome and MAC by using CRISPR/Cas9, resulting in the generation of hCF-MAC containing CHO clones without Cre-loxP recombination and drug selection. Our strategy facilitates rapid chromosome cloning and also contributes to the functional genomic analyses of human chromosomes.

Topics: Animals; Cricetinae; Humans; Mice; Chromosomes, Artificial; Cloning, Molecular; Cricetulus; CRISPR-Cas Systems; DNA; Gene Editing; Induced Pluripotent Stem Cells; Translocation, Genetic

PubMed: 38180813
DOI: 10.1093/nar/gkad1218

Authors: Xinjie Zhuang, Jin Huang, Xiaohu Jin...

OBJECTIVE

To determine the diagnostic features of Robertsonian (Rob) translocation (11; 13) in mice and the mechanisms underlying the effect on spermatogenesis and reproductive decline.

METHODS

A Rob translocation (11; 13) mouse model was established by cross-breeding, and confirmed by chromosome analysis. Chromosome aberrations and translocation patterns were identified in mice with Rob translocation (11; 13) by fluorescence in situ hybridization (FISH). Spermatogenic disorders were investigated at different stages of spermatogenesis. Immunofluorescent analysis was performed on sections of testis and epididymis specimens during spermatogenic meiosis. The weight of the testes and reproductive decline were recorded.

RESULTS

The crossed Rob translocation (11; 13) mouse has 39 chromosomes, including a fusion chromosome (included chromosomes 11 and 13) using dual color FISH. There was no difference in the distribution pattern of SYCP3 and γH2AX in spermatocytes between Rob translocation and wild-type mice; however, round haploid spermatids presented characteristic morphologic changes of apoptosis and the number of haploid spermatids was decreased. Furthermore, the immature germ cells were released into the epididymis and the number of mature sperm was reduced.

CONCLUSIONS

Chromosome aberrations and spermatogenic disorders may result from apoptosis of round haploid spermatids and a reduced number of mature sperm in Rob translocation (11; 13) mice. Abnormal sperm and reduced number of sperm may be one of the main reasons for reproductive decline and male infertility in Rob translocation (11; 13) mice.

Topics: Animals; Apoptosis; Chromosome Aberrations; Chromosomes, Mammalian; Humans; Infertility, Male; Male; Mice; Spermatogenesis; Spermatozoa; Translocation, Genetic

PubMed: 25550810
DOI: No ID Found

Authors: Ioannis Panagopoulos, Kristin Andersen, Marta Brunetti...

BACKGROUND/AIM

Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six reported abnormal karyotypes, losses in chromosome 22 and gains in Xq found by comparative genomic hybridization, and mutation analysis of notch receptor 2 (NOTCH2), NOTCH3, platelet-derived growth factor receptor beta (PDGFRB), and mediator complex subunit 12 (MED12) in a few tumors. Herein, we report the genetic findings in another three angioleiomyomas.

MATERIALS AND METHODS

The tumors were examined using G-banding and karyotyping, RNA sequencing, reverse transcription-polymerase chain reaction, Sanger sequencing, and expression analysis.

RESULTS

The first tumor carried a t(4;5)(p12;q32) translocation resulting in fusion of the cardiac mesoderm enhancer-associated non-coding RNA (CARMN in 5q32) with the TXK tyrosine kinase gene (TXK in 4p12) leading to overexpression of TXK. To our knowledge, this is the first time that a recurrent chromosome translocation and its resulting fusion gene have been described in angioleiomyomas. The second tumor carried a four-way translocation, t(X;3;4;16)(q22;p11;q11;p13) which fused the myosin heavy chain 11 gene (MYH11 in 16p13) with intergenic sequences from Xq22 that mapped a few kilobase pairs distal to the insulin receptor substrate 4 gene (IRS4), resulting in enhanced IRS4 expression. The third angioleiomyoma carried another rearrangement of chromosome band Xq22, t(X;9)(q22;q32), as the sole cytogenetic aberration, but no material was available for further molecular investigation.

CONCLUSION

Our data, together with previously reported abnormal karyotypes in angioleiomyomas, show the presence of two recurrent genetic pathways in this tumor type: The first is characterized by presence of the translocation t(4;5)(p12;q32), which generates a CARMN::TXK chimera. The second is recurrent rearrangement of Xq22 resulting in overexpression of IRS4.

Topics: Humans; Angiomyoma; Comparative Genomic Hybridization; Chromosome Aberrations; Translocation, Genetic; Transcription Factors; Abnormal Karyotype

PubMed: 37889065
DOI: 10.21873/cgp.20405

Authors: R X Wang, H G Zhang, Y Pan...

Balanced reciprocal translocations are associated with reproductive failure. Some reciprocal translocation carriers exhibit azoospermia or oligozoospermia, and an association exists between these chromosomal abnormalities and recurrent abortion. Previous reports have indicated the involvement of chromosome 7 translocations in male infertility and recurrent miscarriage. A translocation breakpoint can occur within an important gene, interrupting its structure and leading to male infertility. However, clinical characteristics resulting from chromosome 7 translocation breakpoints have not been studied. Here, we report such breakpoints and their associated clinical features, to enable informed genetic counseling of carriers. Balanced reciprocal translocations were found in 1.57% of the tested patients. Among these 82 individuals, 14 (17.07%) carried a chromosome 7 translocation, of which, five presented with pregestational infertility and clinical manifestations of oligozoospermia or necrospermia, while nine presented with gestational infertility (i.e., were able to conceive, but often resulting in miscarriage). Breakpoints at 7q31 and 7q36 were associated with pregestational infertility, whereas those at 7p10, 7q21.2, 7q22, and 7q32 were connected to gestational infertility. However, the breakpoint at 7p15 was associated with both. Chromosome 7 translocation carriers with pregestational or gestational infertility should be counseled on chromosomal breakpoints and the various molecular technologies available for assisted reproduction.

Topics: Chromosome Breakage; Chromosomes, Human, Pair 7; Genetic Counseling; Heterozygote; Humans; Karyotyping; Male; Translocation, Genetic

PubMed: 27813606
DOI: 10.4238/gmr15048948

Review

Authors: Ranwei Li, Xiuyang Wang, Shuqiang Feng...

RATIONALE

For the carriers of chromosome reciprocal translocation, the reason why some are fertile and others are infertile remains unclear. Here, we describe 2 patients who are carriers of chromosome 1q21 translocation with azoospermia.

PATIENT CONCERNS

A 29-year-old male and a 33-year-old male presented at the clinic with a diagnosis of infertility.

DIAGNOSIS

Both patients with azoospermia were diagnosed with Routine semen analysis, cytogenetic diagnosis and detection of serum reproductive hormones. The karyotype results of 2 patients were 46,XY,t(1;17)(q21;q23) and 46,XY,t(1;10)(q21;p12), respectively.

INTERVENTIONS

After genetic counseling and informed consent, 1 patient (Case 2) chose microsopic testicular sperm extraction (micro-TESE).

OUTCOMES

After micro-TESE, no sperm was found for the patient. Finally, both patients chose clinical treatment through artificial insemination with donor sperm.

LESSONS

These outcomes suggest that breakpoint at 1q21 should be paid attention by physician in genetic counseling, may harbor some genes associated with spermatogenesis, and deserves further be studied on the function of related genes.

Topics: Adult; Chromosomes, Human, Pair 1; Humans; Infertility, Male; Karyotyping; Male; Spermatogenesis; Translocation, Genetic

PubMed: 31876761
DOI: 10.1097/MD.0000000000018588

Review

Authors: Vassilis Roukos, Tom Misteli

Chromosome translocations are catastrophic genomic events and often play key roles in tumorigenesis. Yet the biogenesis of chromosome translocations is remarkably poorly understood. Recent work has delineated several distinct mechanistic steps in the formation of translocations, and it has become apparent that non-random spatial genome organization, DNA repair pathways and chromatin features, including histone marks and the dynamic motion of broken chromatin, are critical for determining translocation frequency and partner selection.

Topics: Animals; Cell Transformation, Neoplastic; Chromatin; DNA Breaks, Double-Stranded; DNA Repair; Histones; Humans; Mice; Mutation Rate; Saccharomyces cerevisiae; Translocation, Genetic

PubMed: 24691255
DOI: 10.1038/ncb2941

Authors: Yingying Wang, Shouli Feng, Sai Li...

BACKGROUND

We previously reported the development of a set of Gossypium hirsutum-G. australe alien chromosome addition lines. Naturally, however, G. hirsutum-G. australe chromosome exchanges were very limited, impeding the stable transference of useful genes from G. australe (GG genome) into the most cultivated cotton, G. hirsutum (AADD).

RESULTS

In the present report, the pollen from a pentaploid (2n = AADDG) of G. hirsutum-G. australe was irradiated with seven different doses ranging from 10 to 40 Grays and used to pollinate emasculated flowers of G. hirsutum over three consecutive years. Irradiation greatly increased the genetic recombination rates of the G. hirsutum and G. australe chromosomes and a total of 107 chromosome introgression individuals in 192 GISH-negative (with no GISH signal on chromosome) survived individuals, 11 chromosome translocation individuals (containing 12 chromosome translocation events) and 67 chromosome addition individuals were obtained in 70 GISH-positive (with GISH signal(s) on chromosome(s)) survived individuals, which are invaluable for mining desirable genes from G. australe. Multicolor genomic in situ hybridization results showed that there were three types of translocation, whole arm translocation, large alien segment translocation and small alien segment translocation, and that all translocations occurred between the G-genome and the A-subgenome chromosomes in G. hirsutum. We also found that higher doses induced much higher rates of chromosome variation but also greatly lowered the seed viability and seedling survivability.

CONCLUSIONS

Irradiation has been successfully employed to induce chromosome introgressions and chromosome translocations and promote chromosome exchanges between cultivated and wild species. In addition, by balancing the rates of chromosome introgression and translocation to those of seed set, seed germination, and seedling rates in the M1 generation, we conclude that the dosage of 20 Grays is the most suitable. The established methodology may guide the utilization of the tertiary gene pool of Gossypium species such as G. australe in cotton breeding in the future.

Topics: Chromosome Aberrations; Chromosomes, Plant; Germination; Gossypium; Translocation, Genetic

PubMed: 29301494
DOI: 10.1186/s12864-017-4398-7

Authors: Zhenbo Cheng, Yupeng Wang, Lihuang Guo...

BACKGROUND

As one of the most common chromosomal causes, chromosome translocation leads to T-cell acute lymphoblastic leukemia (T-ALL). Ku70 is one of the key factors of error-prone DNA repair and it may end in translocation. So far, the direct correlation between Ku70 and translocation has not been assessed. This study aimed to investigate the association between Ku70 and translocation in human lymphocytes after radiation and T-ALL.

METHODS

Peripheral blood lymphocytes (PBLs) from volunteers and human lymphocyte cell line AHH-1 were irradiated with X-rays to form the chromosome translocations. Phytohemagglutinin (PHA) was used to stimulate lymphocytes. The frequency of translocation was detected by fluorescence in situ hybridization (FISH). Meanwhile, the expression of Ku70 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Furthermore, Ku70 interference, overexpression and chemical inhibition were used in AHH-1 cell lines to confirm the correlation. Finally, the expression of Ku70 in T-ALL samples with or without translocation was detected.

RESULTS

The expression of Ku70 and frequencies of translocation were both significantly increased in PBLs after being irradiated by X-rays, and a positive correlation between the expression (both mRNA and protein level) of Ku70 and the frequency of translocation was detected (r = 0.4877, P = 0.004; r = 0.3038, P = 0.0358 respectively). Moreover, Ku70 interference decreased the frequency of translocations, while the frequency of translocations was not significantly affected after Ku70 overexpression. The expression of Ku70 and frequencies of translocation were both significantly increased in cells after irradiation, combined with chemical inhibition (P < 0.01). The protein level and mRNA level of Ku70 in T-ALL with translocation were obviously higher than T-ALL with normal karyotype (P = 0.009, P = 0.049 respectively).

CONCLUSIONS

Ku70 is closely associated with the frequency of chromosome translocation in human lymphocytes after radiation and T-ALL. Ku70 might be a radiation damage biomarker and a potential tumor therapy target.

Topics: Humans; In Situ Hybridization, Fluorescence; Lymphocytes; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; RNA, Messenger; T-Lymphocytes; Translocation, Genetic

PubMed: 35986335
DOI: 10.1186/s13014-022-02113-3