Y染色体异常对男性生育的影响
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摘要
本研究分析各种异常Y染色体核型及结构上的多态性在特定人群中的发生率,探讨这些异常核型及结构上的多态性所导致的临床效应。亦分析Y染色体微缺失以及各种缺失类型在不育男性中的发生率,并研究不同缺失区域及类型与男性不育各种表型的关系,为男性不育症及复发性流产的病因诊断、治疗及治疗结局的预测提供参考依据。本研究通过分析Y染色体不同微缺失区域及缺失位点类型与男性内分泌水平、睾丸体积及睾丸细胞学结果的关系,以阐明不同缺失区域与位点在精子发生调控中的作用,为精子发生调控机制的研究提供候选基因。通过对6例携带有异常Y染色体亲代的男性后代进行研究,以阐明Y染色体的垂直传递效应,为遗传咨询及辅助生殖技术治疗提供依据。
Background
The Y chromosome consists of a short (Yp) and a long (Yq) arm. The Y chromosome is male specific, 60 megabases in size, consisting of 60 million nucleotides. The abnormality of Y chromosome in quantity and construction maybe results in male infertility, and increase the risk of abortion. Y chromosome microdeletions are the most frequently observed structural abnormalities in the male-specific region of the Y chromosome. Notwithstanding the large body of information gained on the Y chromosome during the last decade, it is still not possible to attribute spermatogenic function to definite genes, because each of the deletions usually removes multiple genes. Consequently, it is not clear whether the resulted phenotype is caused by the loss of all genes in a region or by disruption of a major gene whose expression alone is responsible for spermatogenesis. Furthermore, the known patterns of deletions are variable in details and preclude clear classification of men with a specific type of deletion. In addition, modern artificial reproduction techniques like testicular sperm extraction and intracytoplasmic sperm injection can halp couples, such as azoospermia and oligozoospermia, to overcome infertility. Since the use of these artificial reproductive technologyies can bypass the natural selection of intact spermatozoa, there have been consistent concerns about the possibility of transmitting genetic disorders to the offspring. The scenario is further complicated by the presence of a Y chromosome microdeletion. These structural genetic abnormalities form various genotypes that result in diverse unpredictable phenotypes, warranting further elucidation of their role in infertility and their influence of the assisted reproductive technologies outcomes.
Objective
1. To evaluate the influence of Y chromosome abnormatility and polymorphism in karyotypic analysis on male fertility.
2. To investigate the frequencies of Y chromosome microdeletion in infertile men and the possible association of Y chromosome microdeletion with particular infertile phenotypes. Also, to study the function of different region and STS in AZF on the spermatogenesis.
3. To study the genetic risk for the next generation whose father with abnormal Y chromosome.
Methods
The study population came from 2598 male patients attending genetic consultancy in the Cell Biology Department, Norman Bethune College of Jilin University during 2008.09-2010.12. These male patients were suffering from infertility or miscarriage. Also, 28 fertile men were used as controls. Multiplex polymerase chain reaction (PCR) amplification using nine specific sequencetagged sites (STS) were used to detect Y chromosome microdeletions. Karyotype analyses were performed on peripheral blood lymphocytes with standard G-banding.
Results
1. Karyotype analysis was performed in 2348 male patients. Of 378 patients with abnormal karyotype, 74 patients had abnormal Y chromosome or Y chromosome polymorphic accounting for 3.15% and including 16 patients(0.68%) with abnormal karyotype and 57 patients (2.34%)with Ychromosome polymorphic. Of 31 patients had short Y chromosome accounting for 54.39% in patients with Y chromosome polymorphic and of 18 patients had long Y chromosome accounting for 31.58% in patients with Y chromosome polymorphic. One of the translocations was 45,X,der (Y;13)(q10;q10) and the other was 45,X,der (Y;15)(p?;q11). They are both azoospermia. Of 6 patients had mosaic karyotype: 45X/46,XY, including 3 patients with abnormal Y chromosome. Of 7 patients had 47,XYY, including one patients with 47,XY,+del (Yq12).
2. Of 700 infertile cases, Y chromosome microdeletion were detected in 104 infertile male patients with a frequency of 11.27%, including 56 patients (53.85%)with azoospermia, 23 patients(22.16%) with cryozoospermia, 1 patients(0.96%) with oligozoospermia and 24 patients (23.08%)with severe oligozoospermia.
3. The most frequent microdeletion were in AZFc+d(60.58%), followed by AZFc(18.27%)、AZFb+c+d(10.58%)、AZFb (5.77%)、AZFa+c+d (1.92%)、AZFa(0.96%)and AZFd(0.96%).
4. Among the patients, deletion in sY254 and sY255 (92.31%)was the most common in nine STS detected in our study, followed by sY152(74.07%), sY157(43.27%), sY127(15.38%), sY143(5.77%%), sY134(3.85%)and sY86(2.88%). The deletion in sY84 was not found.
5. In this study, 375 cases of azoospermic patients, 56 patients had Y chromosome microdeletion, including 1 case of removing of AZFa , 4 cases of removing of AZFb, 11 cases of removing of AZFc, 6 cases of removing of AZFb+c+d and 33 cases of removing of AZFc+d. In 138 cases of cryozoospermia, 23 cases had Y chromosome microdeletion, including 1 cases of removing of AZFb, 5 cases of removing of AZFc, 1 case of removing of AZFb+c, 5 cases of removing of AZFb+c+d and 10 cases of removing of AZFc+d. In 143 cases of severe oligozoospermia, 24 cases had Y chromosome microdeletion, including 1 cases of removing of AZFb, 3 cases of removing of AZFc, 1 case of removing of AZFd and 19 cases of removing of AZFc+d. In 32 cases of oligozoospermia, 1 cases had Y chromosome microdeletion in AZFc+d.
6. In present study, 3 patients had Y chromosome microdeletion respectively in AZFa (the loss of sY86 ), AZFd and AZFb+d(the loss of sY143+254+255). AZFb deletion and AZFb+c+d deletion respectively presented 4 kinds of microdeletion, while AZFa+c+d deletion and AZFc+d deletion respectively presented 2 kinds of microdeletion.
7. The detection of Y chromosome microdeletion and hormone were performed in 301 male infertility patients with normal Karyotype including 67 patients in deletion group and 234 patients in non-deletion group. Comparing with non-deletion group, LH and FSH lever in serum in microdeletion group apparently increased(P<0.05), as well as in AZFc+d microdeletion group(P<0.05).
8. The detection of Y chromosome microdeletion and INHB were performed in 194 male infertility patients with normal Karyotype. Comparing with non-deletion group, no difference of the INHB lever in deletion group(P≥0.05).
9. The volume of testis was examined in 223 cases with male infertility with normal Karyotype . Comparing with non-deletion group, the volume of testis in microdeletion group apparently increased(P<0.05), as well as in AZFc+d microdeletion group(P<0.05).
10. Eight patients who showed microdeletions underwent testicular biopsy, and non sperm was found in testicular histology. One patient showed SCOS and removing STS respectively was sY157、sY254 and sY255. In seven patients, maturation arrest was observed at different steps of spermatogenesis, involving four patients with arrest in spermatocytes and three patients with arrest in spermatid.
11. Of 394 patients with male infertility, 354 had normal karyotype and 38 patients had abnormal karyotype. Significant difference in the percentage of patients with abnormal karyotype between non-deletion group and deletion group(P≥0.05). Otherwise, comparing with patients with Y chromosome microdeletion and normal karyotype, the patients with Y chromosome microdeletion and abnormal karyotype had significantly higher risk of azoospermia(P<0.05).
12. In current study, father and sons having the same Ychromosomal abnormality were found in 6 families. Three families had short Y chromosome, and the sons had severe oligozoospermia or dysplasia. Two families had long Y chromosome, and the sons had azoospermia or congenital malformation. One family had 46,XY,Yp+, and the son had normal semen. 4 sons from different family finished the detection of Y chromosome microdeletion, and no abnormalities were observed.
Conclusions
1. The abnormal Karyotype and polymorphism in Y chromosome can result in male infertility, miscarriage and fetal anomaly.
2. Among the genotype about Y chromosome microdeletion, the frequency of AZFc+d deletion was the most high.
3. Y chromosome microdeletion could result in abnormal LH and FSH lever and testis volume, and then result in maturation arrest.
4. The AZFd may by play an important role in spermatogenesis, and its deletion could induce or aggratate maturation arrest.
5. The short Y chromosome could result from the microdeletion of euchromatic region in long arm.
6. There are now seven cases of vertical transmission of abnormal Y chromosome, furthermore, the phenotypes of sons are more severe than their fathers’. This result suggests that the de novo mutation which can lead to more severer phenotypes in offspring than in parental generation could be occurred during vertical trasmisssion.
Background
The Y chromosome consists of a short (Yp) and a long (Yq) arm. The Y chromosome is male specific, 60 megabases in size, consisting of 60 million nucleotides. The abnormality of Y chromosome in quantity and construction maybe results in male infertility, and increase the risk of abortion. Y chromosome microdeletions are the most frequently observed structural abnormalities in the male-specific region of the Y chromosome. Notwithstanding the large body of information gained on the Y chromosome during the last decade, it is still not possible to attribute spermatogenic function to definite genes, because each of the deletions usually removes multiple genes. Consequently, it is not clear whether the resulted phenotype is caused by the loss of all genes in a region or by disruption of a major gene whose expression alone is responsible for spermatogenesis. Furthermore, the known patterns of deletions are variable in details and preclude clear classification of men with a specific type of deletion. In addition, modern artificial reproduction techniques like testicular sperm extraction and intracytoplasmic sperm injection can halp couples, such as azoospermia and oligozoospermia, to overcome infertility. Since the use of these artificial reproductive technologyies can bypass the natural selection of intact spermatozoa, there have been consistent concerns about the possibility of transmitting genetic disorders to the offspring. The scenario is further complicated by the presence of a Y chromosome microdeletion. These structural genetic abnormalities form various genotypes that result in diverse unpredictable phenotypes, warranting further elucidation of their role in infertility and their influence of the assisted reproductive technologies outcomes.
Objective
1. To evaluate the influence of Y chromosome abnormatility and polymorphism in karyotypic analysis on male fertility.
2. To investigate the frequencies of Y chromosome microdeletion in infertile men and the possible association of Y chromosome microdeletion with particular infertile phenotypes. Also, to study the function of different region and STS in AZF on the spermatogenesis.
3. To study the genetic risk for the next generation whose father with abnormal Y chromosome.
Methods
The study population came from 2598 male patients attending genetic consultancy in the Cell Biology Department, Norman Bethune College of Jilin University during 2008.09-2010.12. These male patients were suffering from infertility or miscarriage. Also, 28 fertile men were used as controls. Multiplex polymerase chain reaction (PCR) amplification using nine specific sequencetagged sites (STS) were used to detect Y chromosome microdeletions. Karyotype analyses were performed on peripheral blood lymphocytes with standard G-banding.
Results
1. Karyotype analysis was performed in 2348 male patients. Of 378 patients with abnormal karyotype, 74 patients had abnormal Y chromosome or Y chromosome polymorphic accounting for 3.15% and including 16 patients(0.68%) with abnormal karyotype and 57 patients (2.34%)with Ychromosome polymorphic. Of 31 patients had short Y chromosome accounting for 54.39% in patients with Y chromosome polymorphic and of 18 patients had long Y chromosome accounting for 31.58% in patients with Y chromosome polymorphic. One of the translocations was 45,X,der (Y;13)(q10;q10) and the other was 45,X,der (Y;15)(p?;q11). They are both azoospermia. Of 6 patients had mosaic karyotype: 45X/46,XY, including 3 patients with abnormal Y chromosome. Of 7 patients had 47,XYY, including one patients with 47,XY,+del (Yq12).
2. Of 700 infertile cases, Y chromosome microdeletion were detected in 104 infertile male patients with a frequency of 11.27%, including 56 patients (53.85%)with azoospermia, 23 patients(22.16%) with cryozoospermia, 1 patients(0.96%) with oligozoospermia and 24 patients (23.08%)with severe oligozoospermia.
3. The most frequent microdeletion were in AZFc+d(60.58%), followed by AZFc(18.27%)、AZFb+c+d(10.58%)、AZFb (5.77%)、AZFa+c+d (1.92%)、AZFa(0.96%)and AZFd(0.96%).
4. Among the patients, deletion in sY254 and sY255 (92.31%)was the most common in nine STS detected in our study, followed by sY152(74.07%), sY157(43.27%), sY127(15.38%), sY143(5.77%%), sY134(3.85%)and sY86(2.88%). The deletion in sY84 was not found.
5. In this study, 375 cases of azoospermic patients, 56 patients had Y chromosome microdeletion, including 1 case of removing of AZFa , 4 cases of removing of AZFb, 11 cases of removing of AZFc, 6 cases of removing of AZFb+c+d and 33 cases of removing of AZFc+d. In 138 cases of cryozoospermia, 23 cases had Y chromosome microdeletion, including 1 cases of removing of AZFb, 5 cases of removing of AZFc, 1 case of removing of AZFb+c, 5 cases of removing of AZFb+c+d and 10 cases of removing of AZFc+d. In 143 cases of severe oligozoospermia, 24 cases had Y chromosome microdeletion, including 1 cases of removing of AZFb, 3 cases of removing of AZFc, 1 case of removing of AZFd and 19 cases of removing of AZFc+d. In 32 cases of oligozoospermia, 1 cases had Y chromosome microdeletion in AZFc+d.
6. In present study, 3 patients had Y chromosome microdeletion respectively in AZFa (the loss of sY86 ), AZFd and AZFb+d(the loss of sY143+254+255). AZFb deletion and AZFb+c+d deletion respectively presented 4 kinds of microdeletion, while AZFa+c+d deletion and AZFc+d deletion respectively presented 2 kinds of microdeletion.
7. The detection of Y chromosome microdeletion and hormone were performed in 301 male infertility patients with normal Karyotype including 67 patients in deletion group and 234 patients in non-deletion group. Comparing with non-deletion group, LH and FSH lever in serum in microdeletion group apparently increased(P<0.05), as well as in AZFc+d microdeletion group(P<0.05).
8. The detection of Y chromosome microdeletion and INHB were performed in 194 male infertility patients with normal Karyotype. Comparing with non-deletion group, no difference of the INHB lever in deletion group(P≥0.05).
9. The volume of testis was examined in 223 cases with male infertility with normal Karyotype . Comparing with non-deletion group, the volume of testis in microdeletion group apparently increased(P<0.05), as well as in AZFc+d microdeletion group(P<0.05).
10. Eight patients who showed microdeletions underwent testicular biopsy, and non sperm was found in testicular histology. One patient showed SCOS and removing STS respectively was sY157、sY254 and sY255. In seven patients, maturation arrest was observed at different steps of spermatogenesis, involving four patients with arrest in spermatocytes and three patients with arrest in spermatid.
11. Of 394 patients with male infertility, 354 had normal karyotype and 38 patients had abnormal karyotype. Significant difference in the percentage of patients with abnormal karyotype between non-deletion group and deletion group(P≥0.05). Otherwise, comparing with patients with Y chromosome microdeletion and normal karyotype, the patients with Y chromosome microdeletion and abnormal karyotype had significantly higher risk of azoospermia(P<0.05).
12. In current study, father and sons having the same Ychromosomal abnormality were found in 6 families. Three families had short Y chromosome, and the sons had severe oligozoospermia or dysplasia. Two families had long Y chromosome, and the sons had azoospermia or congenital malformation. One family had 46,XY,Yp+, and the son had normal semen. 4 sons from different family finished the detection of Y chromosome microdeletion, and no abnormalities were observed.
Conclusions
1. The abnormal Karyotype and polymorphism in Y chromosome can result in male infertility, miscarriage and fetal anomaly.
2. Among the genotype about Y chromosome microdeletion, the frequency of AZFc+d deletion was the most high.
3. Y chromosome microdeletion could result in abnormal LH and FSH lever and testis volume, and then result in maturation arrest.
4. The AZFd may by play an important role in spermatogenesis, and its deletion could induce or aggratate maturation arrest.
5. The short Y chromosome could result from the microdeletion of euchromatic region in long arm.
6. There are now seven cases of vertical transmission of abnormal Y chromosome, furthermore, the phenotypes of sons are more severe than their fathers’. This result suggests that the de novo mutation which can lead to more severer phenotypes in offspring than in parental generation could be occurred during vertical trasmisssion.
引文
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