#270960
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that spermatogenic failure-4 (SPGF4) and recurrent pregnancy loss (RPRGL4) are caused by heterozygous mutation in the SYCP3 gene (604759) on chromosome 12q23.
Azoospermia, a condition in which there are no sperm present in the ejaculate, has historically been divided into 2 broad categories, obstructive (e.g., 277180) and nonobstructive. Among the genetically based, inherited nonobstructive causes are defects of spermatogenesis, which may interrupt the development of the sperm at various stages, either before (e.g., 415000) or during meiosis. SPGF4 is a form of azoospermia due to perturbations of meiosis.
For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).
Recurrent Pregnancy Loss
Miscarriage, the commonest complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks' gestation. Recurrent miscarriage, defined as 3 or more consecutive pregnancy losses, affects about 1% of couples; when defined as 2 or more losses, the scale of the problem increases to 5% of all couples trying to conceive (summary by Rai and Regan, 2006).
Pregnancy losses have traditionally been designated 'spontaneous abortions' if they occur before 20 weeks' gestation and 'stillbirths' if they occur after 20 weeks. Subtypes of spontaneous abortions can be further distinguished on the basis of embryonic development and include anembryonic loss in the first 5 weeks after conception (so-called 'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal loss from 10 weeks' gestation through the remainder of the pregnancy. These distinctions are important because the causes of pregnancy loss vary over gestational ages, with anembryonic losses being more likely to be associated with chromosomal abnormalities, for example. Possible etiologies for recurrent pregnancy loss include uterine anatomic abnormalities, cytogenetic abnormalities in the parents or fetus, single gene disorders, thrombophilic conditions, and immunologic or endocrine factors as well as environmental or infectious agents (summary by Warren and Silver, 2008).
For a discussion of genetic heterogeneity of recurrent pregnancy loss, see RPRGL1 (614389).
Chaganti and German (1979) reported a family in which infertility due to azoospermia or oligospermia affected 3 men related through their mothers. Testicular tissue obtained from the 46,XY phenotypically male but azoospermic propositus exhibited normal zygotene and pachytene pairing but premature desynapsis, with a reduced chiasma frequency and degeneration of spermatocytes during the first meiotic division. They postulated that a gene for meiotic disturbance, spermatogenic arrest, and azoospermia was segregating in this family, inherited in either an X-linked recessive or sex-limited autosomal dominant fashion.
Soderstrom and Suominen (1980) examined testicular biopsy specimens from 147 men with the clinical diagnosis of azoospermia or oligospermia. Meiotic arrest was found in 27 cases; closer scrutiny of 7 of the specimens showed that the pattern of meiotic arrest commonly varied in the same specimen, with coexisting areas of normal spermatogenesis and meiotic arrest. Because the timing of the arrest was consistently in the late pachytene stage, with condensation of chromatin along the synaptonemal complex, Soderstrom and Suominen (1980) concluded that there might be a genetic cause for the meiotic arrest.
Chaganti et al. (1980) reported 2 nearly azoospermic sibs of a consanguineous marriage; meiotic cells from a testicular biopsy of the 46,XY phenotypically male proband exhibited asynapsis, defective synaptonemal complex formation, chiasma failure, and degeneration of prophase spermatocytes with asynapsis. The meiotic abnormalities and infertility in this family appeared to comprise an autosomal recessive trait.
Cantu et al. (1981) studied three 46,XY phenotypically male, azoospermic brothers in a sibship of 13 from a consanguineous marriage and found a unique pattern of testicular histology with arrest of spermatogenesis at the pachytene stage of primary spermatocytes.
Recurrent Pregnancy Loss 4
Bolor et al. (2009) studied 2 Japanese women, aged 39 and 29 years, with recurrent pregnancy loss. Each had experienced 3 miscarriages between 6 and 10 weeks of gestation, with no liveborns.
Miyamoto et al. (2003) screened for mutations in the SYCP3 (604759) gene in DNA from 19 unrelated azoospermic patients with maturation arrest and 75 normal pregnancy-proven fertile men. In 2 patients they identified a heterozygous 1-bp deletion (643delA; 604759.0001) that resulted in truncation of the C-terminal, coiled-coil-forming region of the protein. The mutant protein showed greatly reduced interaction with the wildtype protein in vitro and interfered with SYCP3 fiber formation in cultured cells. The results suggested that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein by dominant-negative interference.
Susceptibility to Recurrent Pregnancy Loss
Bolor et al. (2009) analyzed the SYCP3 gene in 26 Japanese women with recurrent pregnancy loss (RPRGL) and identified heterozygosity for a deletion and a point mutation in 2 of the women (604759.0002 and 604759.0003, respectively) that were not found in 150 fertile women. Both mutant proteins were shown to inhibit normal fiber formation of SYCP3 when coexpressed in a heterologous system. This suggested that the heterozygous mutations are likely to form aberrant lateral elements in the synaptonemal complex in a dominant-negative manner, possibly leading to abnormal chromosomal behavior in meiosis I during oogenesis. Bolor et al. (2009) noted that the SYCP3-related phenotype in humans, in which affected males are infertile whereas affected females have recurrent pregnancy loss, is similar to that seen in Sycp3-deficient mice (Yuan et al., 2000; Yuan et al., 2002).
Bolor, H., Mori, T., Nishiyama, S., Ito, Y., Hosoba, E., Inagaki, H., Kogo, H., Ohye, T., Tsutsumi, M., Kato, T., Tong, M., Nishizawa, H., Pryor-Koishi, K., Kitaoka, E., Sawada, T., Nishiyama, Y., Udagawa, Y., Kurahashi, H. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am. J. Hum. Genet. 84: 14-20, 2009. [PubMed: 19110213, images, related citations] [Full Text]
Cantu, J. M., Rivas, F., Hernandez-Jauregui, P., Diaz, M., Cortes-Gallegos, V., Vaca, G., Velazquez, A., Ibarra, B. Meiotic arrest at first spermatocyte level: a new inherited infertility disorder. Hum. Genet. 59: 380-385, 1981. [PubMed: 6800930, related citations] [Full Text]
Chaganti, R. S. K., German, J. Human male fertility, probably genetically determined, due to defective meiosis and spermatogenic arrest. Am. J. Hum. Genet. 31: 634-641, 1979. [PubMed: 574357, related citations]
Chaganti, R. S. K., Jhanwar, S. C., Ehrenbard, L. T., Kourides, I. A., Williams, J. J. Genetically determined asynapsis, spermatogenic degeneration, and infertility in men. Am. J. Hum. Genet. 32: 833-848, 1980. [PubMed: 7446525, related citations]
Miyamoto, T., Hasuike, S., Yogev, L., Maduro, M. R., Ishikawa, M., Westphal, H., Lamb, D. J. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362: 1714-1719, 2003. [PubMed: 14643120, related citations] [Full Text]
Rai, R., Regan, L. Recurrent miscarriage. Lancet 368: 601-611, 2006. [PubMed: 16905025, related citations] [Full Text]
Soderstrom, K.-O., Suominen, J. Histopathology and ultrastructure of meiotic arrest in human spermatogenesis. Arch. Path. Lab. Med. 104: 476-482, 1980. [PubMed: 6893401, related citations]
Warren, J. E., Silver, R. M. Genetics of pregnancy loss. Clin. Obstet. Gynec. 51: 84-95, 2008. [PubMed: 18303502, related citations] [Full Text]
Yuan, L., Liu, J.-G., Hoja, M.-R., Wilbertz, J., Nordqvist, K., Hoog, C. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296: 1115-1118, 2002. [PubMed: 12004129, related citations] [Full Text]
Yuan, L., Liu, J.-G., Zhao, J., Brundell, E., Daneholt, B., Hoog, C. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Molec. Cell 5: 73-83, 2000. [PubMed: 10678170, related citations] [Full Text]
Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 85716005; ORPHA: 399805; DO: 0070176;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q23.2 | Pregnancy loss, recurrent, 4 | 270960 | Autosomal dominant | 3 | SYCP3 | 604759 |
| 12q23.2 | Spermatogenic failure 4 | 270960 | Autosomal dominant | 3 | SYCP3 | 604759 |
A number sign (#) is used with this entry because of evidence that spermatogenic failure-4 (SPGF4) and recurrent pregnancy loss (RPRGL4) are caused by heterozygous mutation in the SYCP3 gene (604759) on chromosome 12q23.
Azoospermia, a condition in which there are no sperm present in the ejaculate, has historically been divided into 2 broad categories, obstructive (e.g., 277180) and nonobstructive. Among the genetically based, inherited nonobstructive causes are defects of spermatogenesis, which may interrupt the development of the sperm at various stages, either before (e.g., 415000) or during meiosis. SPGF4 is a form of azoospermia due to perturbations of meiosis.
For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).
Recurrent Pregnancy Loss
Miscarriage, the commonest complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks' gestation. Recurrent miscarriage, defined as 3 or more consecutive pregnancy losses, affects about 1% of couples; when defined as 2 or more losses, the scale of the problem increases to 5% of all couples trying to conceive (summary by Rai and Regan, 2006).
Pregnancy losses have traditionally been designated 'spontaneous abortions' if they occur before 20 weeks' gestation and 'stillbirths' if they occur after 20 weeks. Subtypes of spontaneous abortions can be further distinguished on the basis of embryonic development and include anembryonic loss in the first 5 weeks after conception (so-called 'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal loss from 10 weeks' gestation through the remainder of the pregnancy. These distinctions are important because the causes of pregnancy loss vary over gestational ages, with anembryonic losses being more likely to be associated with chromosomal abnormalities, for example. Possible etiologies for recurrent pregnancy loss include uterine anatomic abnormalities, cytogenetic abnormalities in the parents or fetus, single gene disorders, thrombophilic conditions, and immunologic or endocrine factors as well as environmental or infectious agents (summary by Warren and Silver, 2008).
For a discussion of genetic heterogeneity of recurrent pregnancy loss, see RPRGL1 (614389).
Chaganti and German (1979) reported a family in which infertility due to azoospermia or oligospermia affected 3 men related through their mothers. Testicular tissue obtained from the 46,XY phenotypically male but azoospermic propositus exhibited normal zygotene and pachytene pairing but premature desynapsis, with a reduced chiasma frequency and degeneration of spermatocytes during the first meiotic division. They postulated that a gene for meiotic disturbance, spermatogenic arrest, and azoospermia was segregating in this family, inherited in either an X-linked recessive or sex-limited autosomal dominant fashion.
Soderstrom and Suominen (1980) examined testicular biopsy specimens from 147 men with the clinical diagnosis of azoospermia or oligospermia. Meiotic arrest was found in 27 cases; closer scrutiny of 7 of the specimens showed that the pattern of meiotic arrest commonly varied in the same specimen, with coexisting areas of normal spermatogenesis and meiotic arrest. Because the timing of the arrest was consistently in the late pachytene stage, with condensation of chromatin along the synaptonemal complex, Soderstrom and Suominen (1980) concluded that there might be a genetic cause for the meiotic arrest.
Chaganti et al. (1980) reported 2 nearly azoospermic sibs of a consanguineous marriage; meiotic cells from a testicular biopsy of the 46,XY phenotypically male proband exhibited asynapsis, defective synaptonemal complex formation, chiasma failure, and degeneration of prophase spermatocytes with asynapsis. The meiotic abnormalities and infertility in this family appeared to comprise an autosomal recessive trait.
Cantu et al. (1981) studied three 46,XY phenotypically male, azoospermic brothers in a sibship of 13 from a consanguineous marriage and found a unique pattern of testicular histology with arrest of spermatogenesis at the pachytene stage of primary spermatocytes.
Recurrent Pregnancy Loss 4
Bolor et al. (2009) studied 2 Japanese women, aged 39 and 29 years, with recurrent pregnancy loss. Each had experienced 3 miscarriages between 6 and 10 weeks of gestation, with no liveborns.
Miyamoto et al. (2003) screened for mutations in the SYCP3 (604759) gene in DNA from 19 unrelated azoospermic patients with maturation arrest and 75 normal pregnancy-proven fertile men. In 2 patients they identified a heterozygous 1-bp deletion (643delA; 604759.0001) that resulted in truncation of the C-terminal, coiled-coil-forming region of the protein. The mutant protein showed greatly reduced interaction with the wildtype protein in vitro and interfered with SYCP3 fiber formation in cultured cells. The results suggested that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein by dominant-negative interference.
Susceptibility to Recurrent Pregnancy Loss
Bolor et al. (2009) analyzed the SYCP3 gene in 26 Japanese women with recurrent pregnancy loss (RPRGL) and identified heterozygosity for a deletion and a point mutation in 2 of the women (604759.0002 and 604759.0003, respectively) that were not found in 150 fertile women. Both mutant proteins were shown to inhibit normal fiber formation of SYCP3 when coexpressed in a heterologous system. This suggested that the heterozygous mutations are likely to form aberrant lateral elements in the synaptonemal complex in a dominant-negative manner, possibly leading to abnormal chromosomal behavior in meiosis I during oogenesis. Bolor et al. (2009) noted that the SYCP3-related phenotype in humans, in which affected males are infertile whereas affected females have recurrent pregnancy loss, is similar to that seen in Sycp3-deficient mice (Yuan et al., 2000; Yuan et al., 2002).
Bolor, H., Mori, T., Nishiyama, S., Ito, Y., Hosoba, E., Inagaki, H., Kogo, H., Ohye, T., Tsutsumi, M., Kato, T., Tong, M., Nishizawa, H., Pryor-Koishi, K., Kitaoka, E., Sawada, T., Nishiyama, Y., Udagawa, Y., Kurahashi, H. Mutations of the SYCP3 gene in women with recurrent pregnancy loss. Am. J. Hum. Genet. 84: 14-20, 2009. [PubMed: 19110213] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.002]
Cantu, J. M., Rivas, F., Hernandez-Jauregui, P., Diaz, M., Cortes-Gallegos, V., Vaca, G., Velazquez, A., Ibarra, B. Meiotic arrest at first spermatocyte level: a new inherited infertility disorder. Hum. Genet. 59: 380-385, 1981. [PubMed: 6800930] [Full Text: https://doi.org/10.1007/BF00295476]
Chaganti, R. S. K., German, J. Human male fertility, probably genetically determined, due to defective meiosis and spermatogenic arrest. Am. J. Hum. Genet. 31: 634-641, 1979. [PubMed: 574357]
Chaganti, R. S. K., Jhanwar, S. C., Ehrenbard, L. T., Kourides, I. A., Williams, J. J. Genetically determined asynapsis, spermatogenic degeneration, and infertility in men. Am. J. Hum. Genet. 32: 833-848, 1980. [PubMed: 7446525]
Miyamoto, T., Hasuike, S., Yogev, L., Maduro, M. R., Ishikawa, M., Westphal, H., Lamb, D. J. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362: 1714-1719, 2003. [PubMed: 14643120] [Full Text: https://doi.org/10.1016/S0140-6736(03)14845-3]
Rai, R., Regan, L. Recurrent miscarriage. Lancet 368: 601-611, 2006. [PubMed: 16905025] [Full Text: https://doi.org/10.1016/S0140-6736(06)69204-0]
Soderstrom, K.-O., Suominen, J. Histopathology and ultrastructure of meiotic arrest in human spermatogenesis. Arch. Path. Lab. Med. 104: 476-482, 1980. [PubMed: 6893401]
Warren, J. E., Silver, R. M. Genetics of pregnancy loss. Clin. Obstet. Gynec. 51: 84-95, 2008. [PubMed: 18303502] [Full Text: https://doi.org/10.1097/GRF.0b013e318161719c]
Yuan, L., Liu, J.-G., Hoja, M.-R., Wilbertz, J., Nordqvist, K., Hoog, C. Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3. Science 296: 1115-1118, 2002. [PubMed: 12004129] [Full Text: https://doi.org/10.1126/science.1070594]
Yuan, L., Liu, J.-G., Zhao, J., Brundell, E., Daneholt, B., Hoog, C. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Molec. Cell 5: 73-83, 2000. [PubMed: 10678170] [Full Text: https://doi.org/10.1016/s1097-2765(00)80404-9]
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