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Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.
The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.
Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.
The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.
The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).
Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.
“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.
The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
The experimental data provided by Feng et al. are unusual in their breadth. Introducing the TUBB8 mutations they identified into HeLa cells, yeast cells, mouse oocytes, and human oocytes disrupted the microtubule networks in all. Depending on the mutation and the specific cell type, these defects ranged from flawed heterodimer assembly to complete obliteration of the microtubule network.
These findings will likely lead to improved diagnoses at fertility clinics. They also offer a potential foundation for discovering other genetic causes of primary female infertility.
Dr. Jurrien Dean is at the Laboratory of Cellular and Developmental Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. He reported having no relevant financial disclosures. These comments are adapted from an editorial by Dr. Dean (N Engl J Med. 2016 Jan 20. doi:10.1056/NEJMe1515512.).
The experimental data provided by Feng et al. are unusual in their breadth. Introducing the TUBB8 mutations they identified into HeLa cells, yeast cells, mouse oocytes, and human oocytes disrupted the microtubule networks in all. Depending on the mutation and the specific cell type, these defects ranged from flawed heterodimer assembly to complete obliteration of the microtubule network.
These findings will likely lead to improved diagnoses at fertility clinics. They also offer a potential foundation for discovering other genetic causes of primary female infertility.
Dr. Jurrien Dean is at the Laboratory of Cellular and Developmental Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. He reported having no relevant financial disclosures. These comments are adapted from an editorial by Dr. Dean (N Engl J Med. 2016 Jan 20. doi:10.1056/NEJMe1515512.).
The experimental data provided by Feng et al. are unusual in their breadth. Introducing the TUBB8 mutations they identified into HeLa cells, yeast cells, mouse oocytes, and human oocytes disrupted the microtubule networks in all. Depending on the mutation and the specific cell type, these defects ranged from flawed heterodimer assembly to complete obliteration of the microtubule network.
These findings will likely lead to improved diagnoses at fertility clinics. They also offer a potential foundation for discovering other genetic causes of primary female infertility.
Dr. Jurrien Dean is at the Laboratory of Cellular and Developmental Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. He reported having no relevant financial disclosures. These comments are adapted from an editorial by Dr. Dean (N Engl J Med. 2016 Jan 20. doi:10.1056/NEJMe1515512.).
Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.
The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.
Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.
The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.
The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).
Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.
“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.
The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.
The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.
Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.
The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.
The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).
Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.
“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.
The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Mutations in the TUBB8 gene cause some female infertility by impairing microtubule behavior, meiotic spindle assembly, and oocyte maturation.
Major finding: Researchers identified seven mutations in the gene TUBB8 that were responsible for oocyte meiosis arrest in seven of 24 families.
Data source: A series of genetic analyses, including assessment of 24 Chinese families with infertility due to arrest of oocyte maturation.
Disclosures: The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
