The Association of Q472H Variant in the KDR Gene with Recurrent Pregnancy Loss in Southern Iran: A Case-control Study

Background: Recurrent spontaneous abortion (RSA) often remains unclear and can be burden for the patient and time consuming for clinician. RSA may initiates from a genetic or non-genetic factors. It is well known that the quality of placental circulation is critical for implantation and embryo development. Because of angiogenic effects of VEGF–KDR pathway on placenta, the genes involved in this pathway (the KDR or VEGFR genes) are thought to be linked with RSA. Objective: The aim of this study was to investigate the relationship between Gln472His (A/T) polymorphism of the KDR gene with RSAs in southern Iran. Materials and Methods: In this case-control study, 50 aborted embryonic tissue obtained from fetuses and 50 umbilical cord blood of newborn babies were studied. Fetal sample from mothers with history of at least two consecutive miscarriages and controls from mothers who had at least one full-term infants born were taken. Genomic DNA was extracted by using PureLink genomic DNA kit (Life Technologies, CA). The Rotor-Gene Q real-Time PCR machine and High-resolution melting curve analysis (HRM) technique were used for genotyping. Results: Based on the AA genotype as reference, it is shown that the T allele (OR = 2.447, 95% CI = 1.095–5.468, p = 0.029) as well as AT heterozygote genotype was significantly associated with an increased risk of miscarriage (OR = 2.824, 95% CI = 1.210-6.673, p = 0.016). Conclusion: A positive correlation between Q472H polymorphism of the KDR gene and RSA may be the cause in southern Iran

Frequency of Factor V Leiden and Prothrombin Polymorphism in South of Iran

Normal hemostasis requires balanced regulation of prothromboticand antithrombotic factors. Inherited alteration of factor Vand prothrombin gene, the G20210A mutation, increases the resistanceof factor V to degradation and booster production ofprothrombin respectively. These alterations can increase hypercoagulabilityleading to thrombotic consequences. We aimed toassess the frequencies of these mutations in a group of the populationof southern Iran. In total, 198 healthy volunteers with theage range of 1-64 years were selected and screened for factor VLeiden and prothrombin mutations using polymerase chain reactionand restriction fragment length polymorphism techniques.The carrier frequencies for factor V Leiden and prothrombin mutationin the studied cohort were 4.1% and 3.07%, respectively.In the studied area, the allele frequency of factor V ishigher than the prothrombin G20210A mutation (0.0204 v0.0153). According to the data and Hardy-Weinberger equation,the total risk of thrombosis caused by homozygosity andheterozygosity of factor V Leiden, prothrombin G20210A mutationand compound heterozygosity of these mutations areabout 1 in 500 individuals

Truncating mutations in UBAP1 cause hereditary spastic paraplegia

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

Purpose: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. Methods: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. Results: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. Conclusion: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder