Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

sharma et al. define a new primary atopic disorder caused by heterozygous gain-of-function variants in STAT6. this results in severe, early-onset allergies, and is seen in 16 patients from 10 families. Anti-IL-4R & alpha; antibody and JAK inhibitor treatment were highly effective.STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. we have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. the cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). all patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and T(H)2 skewing. Precision treatment with the anti-IL-4R & alpha; antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. this study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

MiR-520d expression analysis in breast cancer

Background: Breast cancer is the most common cancer in women. Non-coding RNAs especially miRNAs have important regulatory roles in cancer. MiRNAs are 21-24 nucleotides which have different levels of expression between tumors and normal tissues. In this study, we have analyzed expression level of miR-520d in three different groups of breast cancer.Methods: Fifty nine samples were divided into different groups according to their immunohistochemistry (IHC) classification: estrogen receptor (ER) positive and/or progesterone receptor (PR) positive group (as group I); human epidermal growth factor receptor 2 (HER2) positive group (as group II); and Triple negative group (as group III). After small RNA extraction from tissues, cDNAs were synthesized and Real time RT-PCR carried out using DNA binding dye. Expression levels were analyzed by LinRegPCR and REST software.Results: MiR-520d under- expressed in all of three different groups. The expression ratio in groups I ,II, and III were 0.193, 0.167, 0.21, respectively, but only the result from group II was significant (P=0.017). According to the different clinicopathological status of breast cancer, miR-520d underexpressed significantly not only in patients with metastatic lymph node (P=0.019) but also in patients which have cancer at stage III (P=0.036).  Conclusion: In this study, we found that miR-520d possibly acts as a tumor suppressor. It may be useful for diagnosis of tumor from normal tissue. In addition, miR-520d significantly underexpressed in HER-2 positive group of breast cancers. Therefore, it may be useful as an additional diagnostic test in this group of breast tumors along with other biomarkers

The Spectrum of β -Thalassemia Mutations in Isfahan Province of Iran

Background: β -thalassemia is a common autosomal recessive disorder resulting from over 200 different mutations of beta globin genes. The aim of the present study was to identify the distribution and frequency of the most common β -thalassemia mutations among the population of Isfahan Province in central Iran. Methods: The data presented here were derived from a total of 114 β -thalassemia chromosomes of 18 affected patients and 78 unrelated carriers identified in our screening program. Furthermore, 23 pregnant women were analyzed among couples with a PND request for β -thalassemia. Allele identification was carried out using routine Reverse Dot Blot, ARMS, and genomic sequencing. Results: The most common mutation, IVS-II-I, followed by FSC-36-37, IVS-I-5, FSC-8-9, IVS-I-110, IVS-I,3end; -25bp, IVS-II-745, FSC-8, Cd-39, FSC-22-24, IVS-I-1, Cd-44, IVSII-2,3 (+11/-2), IVS-I-6, and FSC-16, respectively. The present study not only provides a guide for distribution and frequency of both recurrent and uncommon mutations, but also for the first time, reports a rare b-thalassemia mutation, IVSII-2, 3 (+11/-2), in the Isfahan province of Iran. Conclusion: The information presented here could greatly facilitate screening for β -thalassemia and prenatal diagnosis in the province of Isfahan

Advanced molecular approaches pave the road to a clear-cut diagnosis of hereditary retinal dystrophies.

Purpose: The aim of this study was to identify the molecular genetic basis of hereditary retinal dystrophies (HRDs) in five unrelated Iranian families. Methods: Whole exome sequencing and Sanger sequencing were performed in all families. Variants were analyzed using various bioinformatics databases and software. Results: Based on the selected strategies, we identified potentially causative variants in five families with HRDs: the novel homozygous deletion mutation c.586_589delTTTG (p.F196Sfs*56) in the TTC8 gene of family A, the novel homozygous missense mutation c.2389T>C (p.S797P) in the CRB1 gene in family B, the novel homozygous frameshift mutation c.2707dupA (p.S903Kfs*66) in the LRP5 gene in family C, the novel homozygous splice mutation c.584–1G>T in the MERTK gene in family D, and the novel homozygous missense mutation c.1819G>C (p.G607R) rs61749412 in the ABCA4 gene of family E. Conclusions: This study highlights the presence of five novel variants associated with retinal dystrophies in selected Iranian families with hereditary blindness