- Email: [email protected]
Analysis of PBX1 mutations in 192 Chinese women with Müllerian duct abnormalities
Analysis of PBX1 mutations in 192 Chinese women with M€ ullerian duct abnormalities We examined the PBX1 gene in 192 Chinese women with M€ ullerian duct abnormalities and revealed 2 known single nucleotide polymorphisms: c.61G＞A in exon 1 and c.998–1330A>G in intron 7. Future studies in large cohorts of different ethnic populations are warranted to establish definite associations between the PBX1 gene and M€ullerian duct abnormalities. (Fertil Steril 2011;95:2615–7. 2011 by American Society for Reproductive Medicine.) Key Words: Pre–B-cell leukemia homeobox 1, M€ ullerian duct abnormalities, single nucleotide polymorphisms, mutation
During embryogenesis in females, degeneration of the Wolffian ducts and development of the M€ullerian ducts in the absence of testicle hormone production form the upper part of the vagina, uterus, and fallopian tubes (1). M€ullerian duct abnormalities (MDAs) are defined as the congenital absence or severe hypoplasia of the female genital tract. These abnormalities are often accompanied by other organ anomalies, including renal agenesis (25%), skeletal anomalies (10%–12%), and rarely, cardiac or middle ear anomalies (2, 3). The incidence of congenital uterine anomalies is approximately 5 in 1,000 female births (4, 5). Several hypotheses for the origin of MDAs have been previously proposed, including environmental factors, chromosomal abnorJinlong Ma, M.D., Ph.D.a Yingying Qin, M.D., Ph.D.a Wen Liu, M.Sc.a Hua Duan, M.D., Ph.D.b Mingdi Xia, M.Sc.a Zi-Jiang Chen, M.D., Ph.D.a a National Research Center for Assisted Reproductive Technology and Reproductive Genetics, China, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, People’s Republic of China b Department of Obstetrics and Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital University of Medical Sciences, Beijing, People’s Republic of China Received January 31, 2011; revised April 14, 2011; accepted April 19, 2011; published online May 14, 2011. J.M. has nothing to disclose. Y.Q. has nothing to disclose. W.L. has nothing to disclose. H.D. has nothing to disclose. M.X. has nothing to disclose. Z.-J.C. has nothing to disclose. J.M., Y.Q., and W.L. contributed equally to this study. Supported by the National Natural Science Foundation of China (81000236, 30973170) and National Basic Research Program of China (973 program) (2010CB94500, 2007CB947403). Reprint requests: Zi-Jiang Chen, M.D., Ph.D., Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, 250021, People’s Republic of China (E-mail: [email protected]).
0015-0282/$36.00 doi:10.1016/j.fertnstert.2011.04.074
malities, and hormone factors (6–8). A genetic basis has been reported, with function data supporting genes such as the HOXA family (9), WNT family (10), CFTR (11), and AMH (12) expressed along with the differentiating of M€ ullerian ducts. However, the majority of cases are considered to be idiopathic. It is presumed that other genes might participate in the development of MDAs. PBX1 belongs to the PBX family and was initially identified in acute pre–B-cell leukemia. PBX1 is a transcript factor of great interest in regards to malformations found in MDAs. PBX1 is a member of the 3 amino acid loops family of homeodomain factors that are involved in organogenesis during M€ ullerian duct differentiation through regression of the Wolffian ducts (13–15). Pbx1/ mice exhibited severe defects in endocrine cell differentiation and consequent cell malformation (16, 17). As a cofactor of the HOX gene, PBX1 is thought to likely be involved in Mayer-RokitanskyK€ uster-Hauser syndrome, which has a clinical phenotype of M€ ullerian duct development abnormalities. The syndrome is characterized by uterovaginal atresia in an otherwise phenotypically normal female with a normal 46,XX karyotype (18). In this study, we investigated whether perturbation of PBX1 was present in patients with MDAs. We recruited 192 Chinese women with MDAs, including uterine agenesis (n ¼ 19), unicornuate uterus (n ¼ 55), bicornuate uterus (n ¼ 76), and septate uterus (n ¼ 42), from the Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, China, and Department of Obstetrics and Gynecology, Beijing Obstetrics and Gynecology Hospital, Beijing, China. The clinical diagnosis was confirmed by pelvic/abdominal ultrasonography, hysteroscopy, and hysterosalpingogram. In addition, the medical history and physical examination targeted the renal, skeletal, and auditory systems to uncover other possible related defects. All 192 patients had normal female secondary sexual characteristics and 46,XX karyotype. Informed consent for molecular studies was obtained from all participants. The study was approved by the Ethics Committees of Shandong University. After genomic DNA was extracted from peripheral blood samples, the 9 exons coding for PBX1 were amplified using polymerase chain reaction with 9 pairs of PBX1-specific primers. All PBX1
Fertility and Sterility Vol. 95, No. 8, June 30, 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
2615
TABLE 1 Genotype frequencies of SNPs rs2275558 and rs1538488 in Chinese women with MDAs (n [ 192). Allele frequencya
Genotype frequency dbSNP ID Exon 1
rs2275558 c.61G>A
Intron 7
rs1538488 c.998–1330A>G
MDAs (n, %)b
Asian population (%)c
MDAs (%)b
Asian population (%)c
GG (74, 38.0) GA (60, 32.0) AA (58, 30.0) AA (0) AG (0) GG (100)
N/A N/A N/A 0 0 100
G (54.2) A (45.8)
G (52.3) A (47.7)
A (0) G (100)
A (0) G (100)
€llerian duct abnormalities; N/A ¼ not available; SNP ¼ single nucleotide polymorphism. Note: MDA ¼ Mu a Student’s t test: P>.05. b Present study. c International HapMap project database (CSHL-HAPMAP). Ma. Correspondence. Fertil Steril 2011.
primers and detailed information of the polymerase chain reaction conditions are available upon request. The polymerase chain reaction product was first analyzed by agarose gel electrophoresis and then sequenced on an automated sequencer (PRISM 310; Applied Biosystems). Data were analyzed by Student’s t test. Differences in the values were considered significant when P<.05. The HapMap project was used to compare the MDA population with the general Asian population. We analyzed the 9 exons and exon-intron boundaries of the PBX1 gene for variations. Two known single nucleotide polymorphisms (rs2275558 in exon 1 and rs1538488 in intron 7) were identified. The frequencies of the single nucleotide polymorphisms are shown in Table 1. No additional single nucleotide polymorphisms or mutations were found. M€ ullerian duct anomalies consist of a wide range of defects that may vary from patient to patient. Most patients with normal pubertal development are not easily diagnosed until a series of physical examinations are performed. Patients with MDAs have a higher incidence of infertility, spontaneous abortions, fetal intrauterine growth restriction, and retained placenta (19–21). M€ullerian duct anomalies are considered a complex genetic condition affected by multiple genes.
Previous studies have shown that PBX1 plays a crucial role during embryonic development. PBX1 is preferentially expressed in the uterus on embryonic day 14.5, and deficiency of the PBX1 gene in mice results in abnormalities of multiple organs, including inappropriate differentiation of gonads, absence of M€ ullerian ducts, and kidney morphogenesis (22). PBX1 was found to be dispensable for M€ ullerian duct development in transgenic mice (23, 24). Similarly, the inactivation of PBX1 in mammalian female reproductive systems led to the absence of the M€ ullerian duct structures (25, 26). The current study is the first to investigate mutations of PBX1 in a larger cohort with MDAs. The results identified 2 known single nucleotide polymorphisms, which indicates that mutations in the coding sequence of PBX1 are not responsible for MDAs in Chinese women. Future studies using large cohorts of women from different ethnic populations will be required to determine the role of the PBX1 gene in MDAs. Acknowledgments: The authors thank Li You, M.D., of the Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, China, for contribution to patient recruitment and thank all of the participants involved in this study.
REFERENCES 1. Varner RE, Younger JB, Blackwell RE. M€ullerian dysgenesis. J Reprod Med 1985;30: 443–50. 2. Mueller GC, Hussain HK, Smith YR, Quint EH, Carlos RC, Johnson TD, et al. M€ullerian duct anomalies: comparison of MRI diagnosis and clinical diagnosis. AJR Am J Roentgenol 2007;189:1294–302. 3. Ribeiro SC, Tormena RA, Peterson TV, Gonzales Mde O, Serrano PG, Almeida JA, et al. M€ullerian duct anomalies: review of current management. Sao Paulo Med J 2009;127:92–6. 4. Tiker F, Yildirim SV, Barutcu O, Bagis T. Familial M€ ullerian agenesis. Turk J Pediatr 2000;42:322–4. 5. Morcel K, Camborieux L, Guerrier D. Programme de Recherches sur les Aplasies M€ulleriennes. MayerRokitansky-K€ uster-Hauser (MRKH) syndrome. Orphanet J Rare Dis 2007;2:13.
2616
Ma et al.
Correspondence
6. Acien P, Acien M, Sanchez-Ferrer M. Complex malformations of the female genital tract. New types and revision of classification. Hum Reprod 2004;19:2377–84. 7. Pittock ST, Babovic-Vuksanovic D, Lteif A. MayerRokitansky-K€uster-Hauser anomaly and its associated malformations. Am J Med Genet A 2005;135:314–6. 8. Cheroki C, Krepischi-Santos AC, Szuhai K, Brenner V, Kim CA, Otto PA, et al. Genomic imbalances associated with M€ullerian aplasia. J Med Genet 2008;45:228–32. 9. Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod 1997;57:1338–45. 10. Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency—
11.
12.
13.
14.
a clinical phenotype distinct from the Classic MayerRokitansky-K€uster-Hauser syndrome: a case report. Hum Reprod 2007;22:224–9. Radpour R, Gourabi H, Dizaj AV, Holzgreve W, Zhong XY. Genetic investigations of CFTR mutations in congenital absence of vas deferens, uterus, and vagina as a cause of infertility. J Androl 2008;29:506–13. Oppelt P, Strissel PL, Kellermann A, Seeber S, Humeny A, Beckmann MW, et al. DNA sequence variations of the entire anti-M€ullerian hormone (AMH) gene promoter and AMH protein expression in patients with the Mayer-Rokitanski-K€usterHauser syndrome. Hum Reprod 2005;20:149–57. Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 2003;37:123–30. Guerrier D, Mouchel T, Pasquier L, Pellerin I. The Mayer-Rokitansky-K€uster-Hauser syndrome
Vol. 95, No. 8, June 30, 2011
15.
16.
17.
18.
(congenital absence of uterus and vagina)— phenotypic manifestations and genetic approaches. J Negat Results Biomed 2006;5:1. Vallerie AM, Breech LL. Update in M€ullerian anomalies: diagnosis, management, and outcomes. Curr Opin Obstet Gynecol 2010;22:381–7. Dutta S, Gannon M, Peers B, Wright C, BonnerWeir S, Montminy M. PDX: PBX complexes are required for normal proliferation of pancreatic cells during development. Proc Nat Acad Sci U S A 2001;98:1065–70. Kim SK, Selleri L, Lee JS, Zhang AY, Gu X, Jacobs Y, et al. Pbx1 inactivation disrupts pancreas development and in Ipfl-deficient mice promotes diabetes mellitus. Nat Genet 2002;30:430–5. Burel A, Mouchel T, Odent S, Tiker F, Knebelmann B, Pellerin I, et al. Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). J Negat Results Biomed 2006;5:4.
Fertility and Sterility
19. Oppelt P, Renner SP, Kellermann A, Brucker S, Hauser GA, Ludwig KS, et al. Clinical aspects of Mayer-Rokitansky-K€uster-Hauser syndrome: recommendations for clinical diagnosis and staging. Hum Reprod 2006;21:792–7. 20. Doyle JO, Laufer MR. Mayer-Rokitansky-K€usterHauser (MRKH) syndrome with a single septate uterus: a novel anomaly and description of treatment options. Fertil Steril 2009;92:391.e17–9. 21. Creatsas G, Deligeoroglou E, Christopoulos P. Creation of a neovagina after Creatsas modification of Williams vaginoplasty for the treatment of 200 patients with Mayer-RokitanskyK€uster-Hauser syndrome. Fertil Steril 2010;94: 1848–52. 22. Suzuki A, Urushitani H, Sato T, Kobayashi T, Watanabe H, Ohta Y, et al. Gene expression change in the M€ullerian duct of the mouse fetus exposed to diethylstilbestrol in utero. Exp Biol Med (Maywood) 2007;232:503–14.
23. Ferretti E, Villaescusa JC, Di Rosa P, FernandezDiaz LC, Longobardi E, Mazzieri R, et al. Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx and Meis proteins and a pleiotropic embryonic phenotype. Mol Cell Biol 2006;26: 5650–62. 24. Morcel K, Guerrier D, Watrin T, Pellerin I, Leveque J. The Mayer-Rokitansky-K€uster-Hauser (MRKH) syndrome: clinical description and genetics. J Gynecol Obstet Biol Reprod (Paris) 2008;37:539–46. 25. Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 2003;37:123–30. 26. Dintilhac A, Bihan R, Guerrier D, Deschamps S, Bougerie H, Watrin T, et al. PBX1 intracellular localization is independent of MEIS1 in epithelial cells of the developing female genital tract. Int J Dev Biol 2005;49:851–8.
2617
During embryogenesis in females, degeneration of the Wolffian ducts and development of the M€ullerian ducts in the absence of testicle hormone production form the upper part of the vagina, uterus, and fallopian tubes (1). M€ullerian duct abnormalities (MDAs) are defined as the congenital absence or severe hypoplasia of the female genital tract. These abnormalities are often accompanied by other organ anomalies, including renal agenesis (25%), skeletal anomalies (10%–12%), and rarely, cardiac or middle ear anomalies (2, 3). The incidence of congenital uterine anomalies is approximately 5 in 1,000 female births (4, 5). Several hypotheses for the origin of MDAs have been previously proposed, including environmental factors, chromosomal abnorJinlong Ma, M.D., Ph.D.a Yingying Qin, M.D., Ph.D.a Wen Liu, M.Sc.a Hua Duan, M.D., Ph.D.b Mingdi Xia, M.Sc.a Zi-Jiang Chen, M.D., Ph.D.a a National Research Center for Assisted Reproductive Technology and Reproductive Genetics, China, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, People’s Republic of China b Department of Obstetrics and Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital University of Medical Sciences, Beijing, People’s Republic of China Received January 31, 2011; revised April 14, 2011; accepted April 19, 2011; published online May 14, 2011. J.M. has nothing to disclose. Y.Q. has nothing to disclose. W.L. has nothing to disclose. H.D. has nothing to disclose. M.X. has nothing to disclose. Z.-J.C. has nothing to disclose. J.M., Y.Q., and W.L. contributed equally to this study. Supported by the National Natural Science Foundation of China (81000236, 30973170) and National Basic Research Program of China (973 program) (2010CB94500, 2007CB947403). Reprint requests: Zi-Jiang Chen, M.D., Ph.D., Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, 250021, People’s Republic of China (E-mail: [email protected]).
0015-0282/$36.00 doi:10.1016/j.fertnstert.2011.04.074
malities, and hormone factors (6–8). A genetic basis has been reported, with function data supporting genes such as the HOXA family (9), WNT family (10), CFTR (11), and AMH (12) expressed along with the differentiating of M€ ullerian ducts. However, the majority of cases are considered to be idiopathic. It is presumed that other genes might participate in the development of MDAs. PBX1 belongs to the PBX family and was initially identified in acute pre–B-cell leukemia. PBX1 is a transcript factor of great interest in regards to malformations found in MDAs. PBX1 is a member of the 3 amino acid loops family of homeodomain factors that are involved in organogenesis during M€ ullerian duct differentiation through regression of the Wolffian ducts (13–15). Pbx1/ mice exhibited severe defects in endocrine cell differentiation and consequent cell malformation (16, 17). As a cofactor of the HOX gene, PBX1 is thought to likely be involved in Mayer-RokitanskyK€ uster-Hauser syndrome, which has a clinical phenotype of M€ ullerian duct development abnormalities. The syndrome is characterized by uterovaginal atresia in an otherwise phenotypically normal female with a normal 46,XX karyotype (18). In this study, we investigated whether perturbation of PBX1 was present in patients with MDAs. We recruited 192 Chinese women with MDAs, including uterine agenesis (n ¼ 19), unicornuate uterus (n ¼ 55), bicornuate uterus (n ¼ 76), and septate uterus (n ¼ 42), from the Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, China, and Department of Obstetrics and Gynecology, Beijing Obstetrics and Gynecology Hospital, Beijing, China. The clinical diagnosis was confirmed by pelvic/abdominal ultrasonography, hysteroscopy, and hysterosalpingogram. In addition, the medical history and physical examination targeted the renal, skeletal, and auditory systems to uncover other possible related defects. All 192 patients had normal female secondary sexual characteristics and 46,XX karyotype. Informed consent for molecular studies was obtained from all participants. The study was approved by the Ethics Committees of Shandong University. After genomic DNA was extracted from peripheral blood samples, the 9 exons coding for PBX1 were amplified using polymerase chain reaction with 9 pairs of PBX1-specific primers. All PBX1
Fertility and Sterility Vol. 95, No. 8, June 30, 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
2615
TABLE 1 Genotype frequencies of SNPs rs2275558 and rs1538488 in Chinese women with MDAs (n [ 192). Allele frequencya
Genotype frequency dbSNP ID Exon 1
rs2275558 c.61G>A
Intron 7
rs1538488 c.998–1330A>G
MDAs (n, %)b
Asian population (%)c
MDAs (%)b
Asian population (%)c
GG (74, 38.0) GA (60, 32.0) AA (58, 30.0) AA (0) AG (0) GG (100)
N/A N/A N/A 0 0 100
G (54.2) A (45.8)
G (52.3) A (47.7)
A (0) G (100)
A (0) G (100)
€llerian duct abnormalities; N/A ¼ not available; SNP ¼ single nucleotide polymorphism. Note: MDA ¼ Mu a Student’s t test: P>.05. b Present study. c International HapMap project database (CSHL-HAPMAP). Ma. Correspondence. Fertil Steril 2011.
primers and detailed information of the polymerase chain reaction conditions are available upon request. The polymerase chain reaction product was first analyzed by agarose gel electrophoresis and then sequenced on an automated sequencer (PRISM 310; Applied Biosystems). Data were analyzed by Student’s t test. Differences in the values were considered significant when P<.05. The HapMap project was used to compare the MDA population with the general Asian population. We analyzed the 9 exons and exon-intron boundaries of the PBX1 gene for variations. Two known single nucleotide polymorphisms (rs2275558 in exon 1 and rs1538488 in intron 7) were identified. The frequencies of the single nucleotide polymorphisms are shown in Table 1. No additional single nucleotide polymorphisms or mutations were found. M€ ullerian duct anomalies consist of a wide range of defects that may vary from patient to patient. Most patients with normal pubertal development are not easily diagnosed until a series of physical examinations are performed. Patients with MDAs have a higher incidence of infertility, spontaneous abortions, fetal intrauterine growth restriction, and retained placenta (19–21). M€ullerian duct anomalies are considered a complex genetic condition affected by multiple genes.
Previous studies have shown that PBX1 plays a crucial role during embryonic development. PBX1 is preferentially expressed in the uterus on embryonic day 14.5, and deficiency of the PBX1 gene in mice results in abnormalities of multiple organs, including inappropriate differentiation of gonads, absence of M€ ullerian ducts, and kidney morphogenesis (22). PBX1 was found to be dispensable for M€ ullerian duct development in transgenic mice (23, 24). Similarly, the inactivation of PBX1 in mammalian female reproductive systems led to the absence of the M€ ullerian duct structures (25, 26). The current study is the first to investigate mutations of PBX1 in a larger cohort with MDAs. The results identified 2 known single nucleotide polymorphisms, which indicates that mutations in the coding sequence of PBX1 are not responsible for MDAs in Chinese women. Future studies using large cohorts of women from different ethnic populations will be required to determine the role of the PBX1 gene in MDAs. Acknowledgments: The authors thank Li You, M.D., of the Center for Reproductive Medicine, Provincial Hospital affiliated with Shandong University, Jinan, China, for contribution to patient recruitment and thank all of the participants involved in this study.
REFERENCES 1. Varner RE, Younger JB, Blackwell RE. M€ullerian dysgenesis. J Reprod Med 1985;30: 443–50. 2. Mueller GC, Hussain HK, Smith YR, Quint EH, Carlos RC, Johnson TD, et al. M€ullerian duct anomalies: comparison of MRI diagnosis and clinical diagnosis. AJR Am J Roentgenol 2007;189:1294–302. 3. Ribeiro SC, Tormena RA, Peterson TV, Gonzales Mde O, Serrano PG, Almeida JA, et al. M€ullerian duct anomalies: review of current management. Sao Paulo Med J 2009;127:92–6. 4. Tiker F, Yildirim SV, Barutcu O, Bagis T. Familial M€ ullerian agenesis. Turk J Pediatr 2000;42:322–4. 5. Morcel K, Camborieux L, Guerrier D. Programme de Recherches sur les Aplasies M€ulleriennes. MayerRokitansky-K€ uster-Hauser (MRKH) syndrome. Orphanet J Rare Dis 2007;2:13.
2616
Ma et al.
Correspondence
6. Acien P, Acien M, Sanchez-Ferrer M. Complex malformations of the female genital tract. New types and revision of classification. Hum Reprod 2004;19:2377–84. 7. Pittock ST, Babovic-Vuksanovic D, Lteif A. MayerRokitansky-K€uster-Hauser anomaly and its associated malformations. Am J Med Genet A 2005;135:314–6. 8. Cheroki C, Krepischi-Santos AC, Szuhai K, Brenner V, Kim CA, Otto PA, et al. Genomic imbalances associated with M€ullerian aplasia. J Med Genet 2008;45:228–32. 9. Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod 1997;57:1338–45. 10. Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency—
11.
12.
13.
14.
a clinical phenotype distinct from the Classic MayerRokitansky-K€uster-Hauser syndrome: a case report. Hum Reprod 2007;22:224–9. Radpour R, Gourabi H, Dizaj AV, Holzgreve W, Zhong XY. Genetic investigations of CFTR mutations in congenital absence of vas deferens, uterus, and vagina as a cause of infertility. J Androl 2008;29:506–13. Oppelt P, Strissel PL, Kellermann A, Seeber S, Humeny A, Beckmann MW, et al. DNA sequence variations of the entire anti-M€ullerian hormone (AMH) gene promoter and AMH protein expression in patients with the Mayer-Rokitanski-K€usterHauser syndrome. Hum Reprod 2005;20:149–57. Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 2003;37:123–30. Guerrier D, Mouchel T, Pasquier L, Pellerin I. The Mayer-Rokitansky-K€uster-Hauser syndrome
Vol. 95, No. 8, June 30, 2011
15.
16.
17.
18.
(congenital absence of uterus and vagina)— phenotypic manifestations and genetic approaches. J Negat Results Biomed 2006;5:1. Vallerie AM, Breech LL. Update in M€ullerian anomalies: diagnosis, management, and outcomes. Curr Opin Obstet Gynecol 2010;22:381–7. Dutta S, Gannon M, Peers B, Wright C, BonnerWeir S, Montminy M. PDX: PBX complexes are required for normal proliferation of pancreatic cells during development. Proc Nat Acad Sci U S A 2001;98:1065–70. Kim SK, Selleri L, Lee JS, Zhang AY, Gu X, Jacobs Y, et al. Pbx1 inactivation disrupts pancreas development and in Ipfl-deficient mice promotes diabetes mellitus. Nat Genet 2002;30:430–5. Burel A, Mouchel T, Odent S, Tiker F, Knebelmann B, Pellerin I, et al. Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). J Negat Results Biomed 2006;5:4.
Fertility and Sterility
19. Oppelt P, Renner SP, Kellermann A, Brucker S, Hauser GA, Ludwig KS, et al. Clinical aspects of Mayer-Rokitansky-K€uster-Hauser syndrome: recommendations for clinical diagnosis and staging. Hum Reprod 2006;21:792–7. 20. Doyle JO, Laufer MR. Mayer-Rokitansky-K€usterHauser (MRKH) syndrome with a single septate uterus: a novel anomaly and description of treatment options. Fertil Steril 2009;92:391.e17–9. 21. Creatsas G, Deligeoroglou E, Christopoulos P. Creation of a neovagina after Creatsas modification of Williams vaginoplasty for the treatment of 200 patients with Mayer-RokitanskyK€uster-Hauser syndrome. Fertil Steril 2010;94: 1848–52. 22. Suzuki A, Urushitani H, Sato T, Kobayashi T, Watanabe H, Ohta Y, et al. Gene expression change in the M€ullerian duct of the mouse fetus exposed to diethylstilbestrol in utero. Exp Biol Med (Maywood) 2007;232:503–14.
23. Ferretti E, Villaescusa JC, Di Rosa P, FernandezDiaz LC, Longobardi E, Mazzieri R, et al. Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx and Meis proteins and a pleiotropic embryonic phenotype. Mol Cell Biol 2006;26: 5650–62. 24. Morcel K, Guerrier D, Watrin T, Pellerin I, Leveque J. The Mayer-Rokitansky-K€uster-Hauser (MRKH) syndrome: clinical description and genetics. J Gynecol Obstet Biol Reprod (Paris) 2008;37:539–46. 25. Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 2003;37:123–30. 26. Dintilhac A, Bihan R, Guerrier D, Deschamps S, Bougerie H, Watrin T, et al. PBX1 intracellular localization is independent of MEIS1 in epithelial cells of the developing female genital tract. Int J Dev Biol 2005;49:851–8.
2617