Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.      

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Association between paternal age and risk of schizophrenia: a nationwide population–based study

PurposeTo study the association between paternal age and schizophrenia in offspring.MethodsThis report describes a nationwide population-based cohort study from 1997 to 2013. Data from Taiwan’s National Health Insurance Research Database were utilized to answer the research question. A total of 17,649 offspring with schizophrenia were selected from 11 million offspring in the general population. Additionally, we established the offspring without schizophrenia as the comparison group by matching the study cohort by age, gender in a 1:4 ratio (n = 70,596).ResultsThe median age at first presentation with schizophrenia was 20 years (interquartile range (IQR), 17 to 24). Comparison of the schizophrenia and non-schizophrenia groups indicated that father’s age at birth (30.0 (IQR), 27 to 33 vs. 29.0 (IQR), 26 to 32 years), mother’s age at birth (26.0 (IQR), 24 to 29 vs. 26.0 (IQR), 23 to 29 years), paternal schizophrenia (2.6% vs. 0.6%), and maternal schizophrenia (4.4% vs. 0.7%) were all significantly greater in the schizophrenia group. In addition, each 5-year increase in father’s age increased the odds of being diagnosed with schizophrenia (model 1: aOR = 1.22; 95% CI 1.20, 1.24; model 2: aOR = 1.20; 95% CI 1.18, 1.23). Subgroup analysis showed that each 5-year increase in father’s age increased the odds of being diagnosed with schizophrenia in male and female offspring, as well as in offspring of mothers and fathers with or without schizophrenia (aOR = 1.20 to 2.20, all p values < 0.01).ConclusionThis study indicated that advanced paternal age increased the risk of schizophrenia in offspring. Offspring born to fathers older by 5-year increments were at heightened risk of schizophrenia.     

Multivariate analysis of the factors associated with live births during in vitro fertilisation in Southeast Asia: a cross-sectional study of 104,015 in vitro fertilisation records in Taiwan

Purpose

To investigate the factors associated with live births and the interaction between age and the number of embryos transferred after in vitro fertilisation (IVF) treatment.

Methods

This study analyses data from a population-based-assisted reproductive database of all registered artificial reproduction institutions (n = 80) from 2010 to 2016 in Taiwan. The probability of a live birth in correlation with the treatment parameters was measured with multivariate logistic regression analyses using the generalised additive model (GAM) and Pearson’s chi-square exact test.

Results

A total of 104,015 IVF treatments performed between 2010 and 2016 were included in our analysis. From these treatments, 31,467 (30.3%) were successfully delivered, and 40,565 test-tube babies were born. Pearson’s chi-square exact test indicated that parents’ age, cause of infertility, type of ovarian stimulation, additional assisted reproductive technology techniques, donated egg or sperm, fresh or frozen embryo, presence or absence of ovarian hyperstimulation syndrome, and day of embryo transfer were significantly associated with live births after an IVF cycle (p < 0.05). Multiple logistic regression analysis with the GAM revealed that the odds of a live birth with IVF treatment in patients < 34 years of age were 2.55 times higher than that in patients ≥ 45 years of age (odds ratio = 2.55, 95% confidence interval = 1.69–2.90) for patients who underwent a single-embryo transfer (SET); a similar pattern was observed when two or more embryos were transferred. Egg donation, the assisted hatching technique, oral ovarian stimulation agents, and implantation of frozen embryos during SET were shown to improve the chance of a live birth by 29–90%. Implantation of the embryo after the 5th day of culture yielded the highest odds of a live birth. The interaction plot revealed that maternal age, especially < 40 years, was associated with the probability of a live birth. SET and double-embryo transfer showed similar associations with the probability of a live birth across age groups. Transferring more than two embryos might reduce the probability of a live birth during IVF treatment for women ≥ 40 years of age.

Conclusions

Implanting a greater number of embryos did not improve the age-related decrease in fertility for patients undergoing IVF. Therefore, we suggested that ≤ 2 blastocysts could be transferred during IVF treatments for women ≥ 40 years. Transferring a blastocyst on day 5 of culture was associated with a significant increase in the odds of a live birth resulting from IVF.