Molecular analysis of disorders of gonadal development
Zusammenfassung der Projektergebnisse
POF/ODG: By using commercially available arrays 133 novel CNVs were detected in a cohort of 153 patients (96 POF and 57 ODG). Three recurrent CNVs delineate novel candidate genes for POF/ODG. - Using customized arrays 20 potentially pathogenic rearrangements in WT1, NANOS3, FIGLA, LARS2, DMRT1 and DIAPH2 were found. We can show that mutations of LARS2 are not only associated with Perrault syndrome but also in non-syndromic POF. - Gene panel analysis results in the identification of the causative mutation in 24% of the analysed patients. Our findings emphasize the role of STAG3, HFM1, LARS2, SF1, FSHR, MCM8 and WT1 for POF/ODG. Furthermore, we provide evidence for digenic inheritance in some cases (heterozygosity for FSHR and SF1 mutation in one patient, heterozygosity for FSHR and FSHB mutation in another patient) in POF/ODG. XY-GD: We could show that mutations of WT1 cause not only XY gonadal dysgenesis bot also isolated hypospadias or cryptorchidism. - SF1 mutations are detected in 7% of XY GD and in patients with severe oligozoospermia and azoospermia. - We could show that DMRT1 mutations are not only associated with XY GD but also with ovotestis and male infertility. - We provide evidence that different CNVs upstream of SOX9 cause XY GD or SRY-negative XX-maleness.
Projektbezogene Publikationen (Auswahl)
- (2008) Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mut 29:59-64
Köhler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schröder V, Biebermann H, Schnabel D, Grüters A, Achermann JC
(Siehe online unter https://doi.org/10.1002/humu.20588) - (2010) Copy number variants in premature ovarian failure and ovarian dysgenesis. Sex Dev 4:225-32
Ledig S, Röpke A, Wieacker P
(Siehe online unter https://doi.org/10.1159/000314958) - (2010) Mutations of the SRY-responsive enhancer of SOX9 are uncommon in XY gonadal dysgenesis. Sex Dev 4:321-5
Georg I, Bagheri-Fam S, Knower KC, Wieacker P, Scherer G, Harley VR
(Siehe online unter https://doi.org/10.1159/000320142) - (2010) Severe XIST hypomethylation clearly distinguishes (SRY+) 46,XX-maleness from Klinefelter syndrome. Eur J Endocrinol 162:169-75
Poplinski A, Wieacker P, Kliesch S, Gromoll J
(Siehe online unter https://doi.org/10.1530/eje-09-0768) - (2010) Translocation and deletion around SOX9 in a patient with acampomelic campomelic dysplasia and sex reversal. Sex Dev 4:143-9
Jakubiczka S, Schröder C, Ullmann R, Volleth M, Ledig S, Gilberg E, Kroisel P, Wieacker P
(Siehe online unter https://doi.org/10.1159/000302403) - (2011) Analysis of the Wilms' tumor suppressor gene (WT1) in patients 46,XY disorders of sex development. J Clin Endocrinol Metab 96:E1131-6
Köhler B, Biebermann H, Friedsam V, Gellermann J, Maier RF, Pohl M, Wieacker P, Hiort O, Grüters A, Krude H
(Siehe online unter https://doi.org/10.1210/jc.2010-2804) - (2011) Bcar3 is expressed in sertoli cells and germ cells of the developing testis in mice. Sex Dev 5:197-204
Pennekamp P, Feldner S, Seesing FJ, Psathaki OE, Schöler HR, Wieacker P, Dworniczak B
(Siehe online unter https://doi.org/10.1159/000328820) - (2011) Copy number variants in patients with severe oligozoospermia and Sertoli-cell-only syndrome. PLoS One 29; 6:e19426
Tüttelmann F, Simoni M, Kliesch S, Ledig S, Dworniczak B, Wieacker P, Röpke A
(Siehe online unter https://doi.org/10.1371/journal.pone.0019426) - (2011) Ultrastructural characterization of mouse embryonic stem cell-derived oocytes and granulosa cells. Stem Cells Dev 20:2205-15
Psathaki OE, Hübner K, Sabour D, Sebastiano V, Wu G, Sugawa F, Wieacker P, Pennekamp P, Schöler HR
(Siehe online unter https://doi.org/10.1089/scd.2010.0575) - (2012) Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development. Eur J Endocrinol 167:119-24
Ledig S, Hiort O, Wünsch L, Wieacker P
(Siehe online unter https://doi.org/10.1530/EJE-12-0136) - (2013) Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males. Eur J Hum Genet 21:1012-5
Röpke A, Tewes AC, Gromoll J, Kliesch S, Wieacker P, Tüttelmann F
(Siehe online unter https://doi.org/10.1038/ejhg.2012.290) - (2013) Genetic aspects of fertility disorders. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 58: 1642-52
Wieacker P
(Siehe online unter https://doi.org/10.1007/s00103-013-1860-9) - (2013) Mosaicism for an unbalanced Y;21 translocation in an infertile man: a case report. J Assist Reprod Genet 30:1553-8. Tewes AC, Ledig S, Tüttelmann F, Kliesch S, Wieacker P (2014) DMRT1 mutations are rarely associated with male infertility. Fertil Steril 102:816-20
Röpke A, Stratis Y, Dossow-Scheele D, Wieacker P, Kliesch S, Tüttelmann F
(Siehe online unter https://doi.org/10.1007/s10815-013-0122-y) - (2015) Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development. J Med Genet 52:240-7
Kim GJ, Sock E, Buchberger A, Just W, Denzer F, Hoepffner W, German J, Cole T, Mann J, Seguin JH, Zipf W, Costigan C, Schmiady H, Rostásy M, Kramer M, Kaltenbach S, Rösler B, Georg I, Troppmann E, Teichmann AC, Salfelder A, Widholz SA, Wieacker P, Hiort O, Camerino G, Radi O, Wegner M, Arnold HH, Scherer G
(Siehe online unter https://doi.org/10.1136/jmedgenet-2014-102864) - (2015) Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation 46,X,t(X;3)(q21.1;q21.3). Sex Dev 9:86-90
Ledig S, Preisler-Adams S, Morlot S, Liehr T, Wieacker P
(Siehe online unter https://doi.org/10.1159/000373906)
