Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombination involving two recombination hotspots.

To date, mutations in two genes, SPATA16 and DPY19L2, have been identified as responsible for a severe teratozoospermia, namely globozoospermia. The two initial descriptions of the DPY19L2 deletion lead to a very different rate of occurrence of this mutation among globospermic patients. In order to better estimate the contribution of DPY19L2 in globozoospermia, we screened a larger cohort including 64 globozoospermic patients. Twenty of the new patients were homozygous for the DPY19L2 deletion, and 7 were compound heterozygous for both this deletion and a point mutation. We also identified four additional mutated patients. The final mutation load in our cohort is 66.7% (36 out of 54). Out of 36 mutated patients, 69.4% are homozygous deleted, 19.4% heterozygous composite and 11.1% showed a homozygous point mutation. The mechanism underlying the deletion is a non-allelic homologous recombination (NAHR) between the flanking low-copy repeats. Here, we characterized a total of nine breakpoints for the DPY19L2 NAHR-driven deletion that clustered in two recombination hotspots, both containing direct repeat elements (AluSq2 in hotspot 1, THE1B in hotspot 2). Globozoospermia can be considered as a new genomic disorder. This study confirms that DPY19L2 is the major gene responsible for globozoospermia and enlarges the spectrum of possible mutations in the gene. This is a major finding and should contribute to the development of an efficient molecular diagnosis strategy for globozoospermia.

The association of reproductive senescence with mitochondrial quantity, function, and DNA integrity in human oocytes at different stages of maturation.

OBJECTIVE: To determine the impact of reproductive aging on oocyte mitochondrial quantity, function, and DNA (mtDNA) integrity. DESIGN: Prospective observational study. SETTING: IVF clinic in a tertiary academic care center. PATIENT(S): One hundred two oocytes from 32 women undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adenosine triphosphate (ATP) levels, mtDNA number, and mtDNA deletion occurrence in individual oocytes. RESULT(S): Oocyte ATP content increases with maturation (786 ± 87 fmol, 1,037 ± 57 fmol, and 1,201 ± 59 fmol for prophase 1 [P1], metaphase 1 [M1], and metaphase 2 [M2] oocytes, respectively), whereas mtDNA copy numbers do not change (64,500 ± 20,440, 180,000 ± 44,040, and 143,000 ± 31,210 for P1, M1, and M2 oocytes, respectively). Stepwise multiple regression analysis identified developmental stage as a determinant of oocyte ATP, whereas number of oocytes retrieved and cycle day 3 FSH level were determinants of mtDNA copy number. Of the 15 oocytes found to possess the 5-kb mtDNA deletion, 10 were arrested or degenerated oocytes. CONCLUSION(S): Although no direct association was found between female age and oocyte mitochondrial quantity and function, the number of mitochondria was predicted by ovarian reserve indicators. As the oocyte matures, ATP content increases.

Total quality improvement in the IVF laboratory: choosing indicators of quality.

The purpose of this paper is to describe a programme of total quality improvement (TQI) within the IVF laboratory and to provide specific examples of indicators that could be used in such a TQI programme. Although TQI is sometimes confused with quality control (QC) and quality assurance (QA), there are major differences between the three quality plans: (i) QC is an activity designed to ensure that a specific element within the laboratory is functioning correctly; (ii) QA is a comprehensive programme designed to looks at a laboratory as a whole and to identify problems or errors that exist in an attempt to improve the entire process; (iii) TQI is also a comprehensive monitoring process designed not only to detect and eliminate problems, but also to enhance a laboratory's performance by exploring innovation and developing flexibility and effectiveness in all processes. Indicators used in a TQI plan should be objective, relevant to the laboratory, and measure a broad range of specific events or aspects of treatment that reflect the quality of care. Threshold values for each of the indicators should be based on how the specific protocols used in the laboratory impact the outcomes and the nature of the indicators on quality of care.