FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation.

The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.

Bilateral ovarian agenesis and the presence of the testis-specific protein 1-Y-linked gene: two new features of Mayer-Rokitansky-Küster-Hauser syndrome.

OBJECTIVE: To describe the clinical and laboratory features of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) and to provide evidence for its etiology. DESIGN: Case report. SETTING: General hospital. PATIENT(S): Six consecutive cases of MRKH over a period of 12 months. INTERVENTION(S): Endocrine evaluation was performed. Genital system abnormalities were studied by pelvic ultrasound, magnetic resonance imaging, and laparoscopy; associated congenital anomalies by bone studies and intravenous pyelogram; and presence of Y chromosome material by karyotype and polymerase chain reaction (PCR and nested PCR). MAIN OUTCOME MEASURE(S): Clinical and laboratory features of MRKH and presence of Y chromosome genes. RESULT(S): Endocrine evaluation was normal in five patients. One woman revealed hypergonadotropic hypogonadism due to bilateral absence of gonads. Four patients had symmetric (type A) and two had asymmetric uterine remnants and fallopian tubes (type B). Renal and skeletal malformations were present in both types of MRKH. Karyotype was 46,XX in all patients. Although PCR was negative, nested PCR revealed the testis specific protein 1-Y-linked (TSPY) gene in two women. CONCLUSION(S): Skeletal and renal malformations may be present in both MRKH subtypes. Gonadal absence may coexist with the syndrome. This is the first report that detects Y-chromosome genes in patients with MRKH.