IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

Polymorphic erythema associated with mycoplasma pneumoniae

Male child, 6 and a half years old, followed for psychomotor delay from the age of 2 years with diagnosis of epilepsy put on sodium valproate for 3 years and in the absence of seizure control carbamazepine was added 2 months before admission. The patient had presented 5 days before his consultation a generalized erythematous rash with edemas of two lower limbs, a dry cough and a fever. He was initially treated as a meningococcemia. On skin examination: generalized erythematous lesions with a rosette appearance, vesicular lesions in the lips. On admission to the service, the patient was put on acilovir, josamycin with discontinuation of carbamazepine. HSV 1 and 2 serology returned negative. Mycoplasma serology was positive for IgM and negative for IgG. The chest X-ray was normal. The skin biopsy was in favor of superficial dermatitis. The evolution was favorable with progressive disappearance of the lesions. Aciclovir was discontinued due to the rapid improvement and negativity of serology and josamycin was discontinued after 14 days of treatment. The general condition improved in 48 hours and the skin lesions disappeared in 15 days

In Silico Analyses of All STAT3 Missense Variants Leading to Explore Divergent AD-HIES Clinical Phenotypes

Autosomal dominant hyper-IgE syndrome (AD-HIES) is linked to dominant negative mutations of the STAT3 protein whose molecular basis for dysfunction is unclear and presenting with a variety of clinical manifestations with only supportive treatment. To establish the relationship between the impact of STAT3 mutations in different domains and the severity of the clinical manifestations, 105 STAT3 mutations were analyzed for their impact on protein stability, flexibility, function, and binding affinity using in Silico approaches. Our results showed that 73% of the studied mutations have an impact on the physicochemical properties of the protein, altering the stability, flexibility and function to varying degrees. In particular, mutations affecting the DNA binding domain (DBD) and the Src Homology 2 (SH2) have a significant impact on the protein structure and disrupt its interaction either with DNA or other STAT3 to form a heterodomain complex, leading to severe clinical phenotypes. Collectively, this study suggests that there is a close relationship between the domain involving the mutation, the degree of variation in the properties of the protein and the degree of loss of function ranging from partial loss to complete loss, explaining the variability of clinical manifestations between mild and severe

Large scale genomic analysis of 3067 SARS-CoV-2 genomes reveals a clonal geo-distribution and a rich genetic variations of hotspots mutations.

In late December 2019, an emerging viral infection COVID-19 was identified in Wuhan, China, and became a global pandemic. Characterization of the genetic variants of SARS-CoV-2 is crucial in following and evaluating it spread across countries. In this study, we collected and analyzed 3,067 SARS-CoV-2 genomes isolated from 55 countries during the first three months after the onset of this virus. Using comparative genomics analysis, we traced the profiles of the whole-genome mutations and compared the frequency of each mutation in the studied population. The accumulation of mutations during the epidemic period with their geographic locations was also monitored. The results showed 782 variants sites, of which 512 (65.47%) had a non-synonymous effect. Frequencies of mutated alleles revealed the presence of 68 recurrent mutations, including ten hotspot non-synonymous mutations with a prevalence higher than 0.10 in this population and distributed in six SARS-CoV-2 genes. The distribution of these recurrent mutations on the world map revealed that certain genotypes are specific to geographic locations. We also identified co-occurring mutations resulting in the presence of several haplotypes. Moreover, evolution over time has shown a mechanism of mutation co-accumulation which might affect the severity and spread of the SARS-CoV-2. The phylogentic analysis identified two major Clades C1 and C2 harboring mutations L3606F and G614D, respectively and both emerging for the first time in China. On the other hand, analysis of the selective pressure revealed the presence of negatively selected residues that could be taken into considerations as therapeutic targets. We have also created an inclusive unified database (http://covid-19.medbiotech.ma) that lists all of the genetic variants of the SARS-CoV-2 genomes found in this study with phylogeographic analysis around the world

Table indicating the clinical presentations of TB recorded in the fifty patients.

<p>The two patients presenting with IL-12Rβ1 deficiency are in bold. N means number and age is indicated in years.</p

Mendelian mutations in <i>IL12RB1</i> leading to severe tuberculosis in two kindreds.

<p><b>A</b>. Pedigree of the two families (A and B) with IL-12Rβ1 deficiency. Each generation is designated by a roman numeral (I–II), and each individual by an Arabic numeral. The double lines connecting the parents indicate consanguinity. The probands are indicated by an arrow, with black indicating <i>Mycobacterium tuberculosis</i> disease status. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?”. <b>B</b>. Electrophoregram showing the genomic sequences of exons 9 and 5 in patients 1 and 2, respectively, compared with a control sequence. <b>C</b>. Schematic diagram of the coding region of the IL-12Rβ1 chain containing 17 coding exons and encoding a 662-amino acid protein with a leader sequence (exon1, L), extracellular domain (exons 2 to 13, EC), transmembrane domain (exon 14, TM) and an intracellular cytoplasmic domain (exons 15 to 17, IC). Published and unpublished mutations are indicated as follows: missense mutations are shown in purple, nonsense mutations are shown in red and complex mutations are shown in brown. Splicing mutations are shown in blue, large deletions are shown in green, insertions are shown in orange, and duplication is shown in magenta. * The 700+362_1619-944del mutation is the only mutation resulting in at the expression of a protein at the cell surface. Mutations of P1 (K305X) and P2 (R173W) are underlined. <b>D</b>. Chest X ray of patient 1 showing the localization of the disease.</p