The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans

Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval

The new “dual osteotomy”: combined open wedge and tibial tuberosity anteriorisation osteotomies

The high frequency with which medial compartment osteoarthritis is associated with patellofemoral osteoarthritis makes the addition of tibial tuberosity anteriorisation to high tibial osteotomy an appealing solution, despite the discouraging previously reported long-term results when tubercle anteriorisation was combined with a Coventry closed wedge technique. We conducted a prospective study of a new osteotomy combination: “the dual osteotomy”. An open wedge high tibial osteotomy was combined with 1- to 1.5-cm Maquet-like tibial tuberosity anteriorisation. Thirty-four knees in 30 patients underwent surgery, including ten knees in nine male patients and 24 knees in 21 female patients with a mean age of 45 years (age range 34−58 years). All patients had varus medial compartment osteoarthritis and patellofemoral osteoarthritis with preoperative anatomical tibiofemoral angle exceeding 5°. Twenty-four months after surgery, final evaluation detected improvement in the Knee Society clinical rating system function score from a mean of 61.3 (range 30−80) preoperatively to a mean of 87.3 (range 50−100) postoperatively and in the knee pain score from 27.3 (range 10−30) to 47 (range 30−50) postoperatively. Based on the rating system, at final follow-up, 70% of patients experienced no pain, 13% had mild or occasional pain, 10% had pain on stairs only, and 7% had pain during walking and on stairs. Anatomical tibiofemoral angles from 0 to 10° valgus were achieved in 91% of operated knees, and union was achieved in all cases within six to twelve weeks after surgery. The dual osteotomy was effective in the short term in cases of medial compartment osteoarthritis associated with patellofemoral osteoarthritis