Heterozygous Gain Research Articles

Addressing the Challenges of Treating Patients with Heterozygous Gain of Function Mutations.

Addressing the Challenges of Treating Patients with Heterozygous Gain of Function Mutations.

Review of patients with achondroplasia: a single-center's experience with follow-up and associated morbidities

Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005–2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies.

Evolocumab & Inclisiran dual therapy for further LDL lowering in a very high cardiovascular risk Familial Hypercholesterolaemia patient with heterozygous gain of function PCSK9 mutation

Evolocumab & Inclisiran dual therapy for further LDL lowering in a very high cardiovascular risk Familial Hypercholesterolaemia patient with heterozygous gain of function PCSK9 mutation

Two cases of successful sirolimus treatment for patients with activated phosphoinositide 3-kinase δ syndrome 1

BackgroundActivated phosphoinositide3-kinase (PI3K) δ syndrome 1 (APDS1) is a novel inborn errors of immunity (IEIs) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD). APDS1 has a spectrum of clinical manifestations. Recurrent respiratory infections, lymphoproliferation, hepatosplenomegaly, hyper-IgM syndrome and autoimmunity are the common symptoms of this disease.Case PresentationPatient 1 presented with recurrent respiratory infections, hepatosplenomegaly and hyper-IgM syndrome. Patient 2 developed early onset systemic lupus erythematosus (SLE)-like disease with resistant thrombocytopenia. c.3061 G > A and c.2314G > A variants in the PIK3CD gene were detected by whole exome sequencing in two patients respectively. c.2314G > A variant in PIK3CD gene of patient 2 is a newly report. After genetic diagnosis, two patients received sirolimus treatment and sirolimus alleviated clinical manifestations, including hepatosplenomegaly in patient 1 and thrombocytopenia in patient 2.ConclusionGenetics diagnosis should be considered in patients with complicated clinical manifestations with no or insufficient response to the conventional therapies. If whole exome sequencing suggests a variant in PIK3CD gene, sirolimus may relieve hepatosplenomegaly and resistant thrombocytopenia. This is the first report of c.2314G > A variant in PIK3CD gene.

Red blood cell proteomics reveal remnant protein biosynthesis and folding pathways in PIEZO1-related hereditary xerocytosis.

Hereditary xerocytosis is a dominant red cell membrane disorder characterized by an increased leak of potassium from the inside to outside the red blood cell membrane, associated with loss of water leading to red cell dehydration and chronic hemolysis. 90% of cases are related to heterozygous gain of function mutations in PIEZO1, encoding a mechanotransductor that translates a mechanical stimulus into a biological signaling. Data are still required to understand better PIEZO1-HX pathophysiology. Recent studies identified proteomics as an accurate and high-input tool to study erythroid progenitors and circulating red cell physiology. Here, we isolated red blood cells from 5 controls and 5 HX patients carrying an identified and pathogenic PIEZO1 mutation and performed a comparative deep proteomic analysis. A total of 603 proteins were identified among which 56 were differentially expressed (40 over expressed and 16 under expressed) between controls and HX with a homogenous expression profile within each group. We observed relevant modifications in the protein expression profile related to PIEZO1 mutations, identifying two main "knots". The first contained both proteins of the chaperonin containing TCP1 complex involved in the assembly of unfolded proteins, and proteins involved in translation. The second contained proteins involved in ubiquitination. Deregulation of proteins involved in protein biosynthesis was also observed in in vitro-produced reticulocytes after Yoda1 exposure. Thus, our work identifies significant changes in the protein content of PIEZO1-HX erythrocytes, revealing a "PIEZO1 signature" and identifying potentially targetable pathways in this disease characterized by a heterogeneous clinical expression and contra-indication of splenectomy.

Real-World Outcomes of IDH Mutant AML Patients Treated with or without IDH Inhibitors

Background: The molecular landscape of acute myeloid Leukemia (AML) is heterogeneous, yet only a few mutations are targetable. Mutations in the isocitrate dehydrogenase genes (IDH1, IDH2) are heterozygous gain of function point mutations with an approximate frequency of 20%. FDA approved IDH2 inhibitor enasidenib in 2017 and IDH1 inhibitor ivosidenib in 2018 for adults with relapsed/refractory (R/R) IDH2 and IDH1MT AML. In May 2022, FDA approved ivosidenib combined with azacitidine for adults aged 75 years or older with newly diagnosed AML who cannot undergo intensive induction chemotherapy. Since IDH inhibitors (IDHi) have been in clinical use within and outside clinical trials for the last few years, we sought to retrospectively analyze our experience and clinical outcomes of patients with IDH mutations who were treated with/without IDHi at our center, especially there is some recent evidence of better response to venetoclax based therapy for patients with IDH mutations. Methods: We included all patients diagnosed with a myeloid neoplasm with IDH1 or IDH2 or both mutations as identified by targeted Next Generation Sequencing using the commercially available Illumina TruSight Myeloid Panel and were treated between October 2014 and September 2021. Baseline demographic and clinical characteristics were noted. The Chi-square test was used to study various parameters as described in the results, and Kaplan-Meier curves were used for survival analyses. Results: Among 65 patients with myeloid neoplasms, 53 (82%) had AML, 8 (12%) had Myelodysplastic syndrome, 2 (3%) had Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), 1 (1.5%) had essential thrombocythemia, and 1 (1.5%) had myelofibrosis secondary to polycythemia vera. Of the 65, 54% (35/65) were male, and the median age at disease diagnosis was 65 years [range, 35-97]. 42% (27/65) in the cohort had IDH1 mutation, 55% (36/65) had IDH2 mutation, and 3% (2/65) had both. Only 29% (19/65) of patients in the cohort received IDHi therapy, and all had AML. 12 (63%) were female. 15 (79%) patients received IDHi therapy in the R/R setting and 4 (21%) in the first line. The median age of patients receiving IDHi was 66 years [range, 44-80]. Of the 19 patients who received IDHi, 6 (32%) achieved complete remission (CR), 2 (10%) achieved complete remission with incomplete count recovery (CRi), 1 (5%) had a partial response (PR), and 10 (53%) had refractory disease. The median time to best response was 3.5 months [range, 0.3-11.25]. IDHi-induced differentiation syndrome (DS) was reported in 6 patients (32%); 4 (21%) who developed DS received Olutasidenib, and 2 (11%) received Enasidenib. Three patients (50%) developed severe DS, two of which died from it. One had moderate DS, and 2 had indeterminate DS. All patients with DS were treated with medication discontinuation and intravenous dexamethasone. Median overall survival for the IDHi group was 28.6 months (95% CI 16.0-41.3) and 30.4 months (95% CI 5.9-54.9) for the non-IDHi group (p = 0.363). Conclusion: Only a minority of patients with IDHMT AML had received IDHi-based therapy, which is attributed to patients diagnosed and treated before the FDA approval. Surprisingly, the median survival for patients who didn't receive IDHi therapy seemed not different, underscoring the other therapies' effects, including the influence of the venetoclax-based regimen. More extensive randomized studies are needed to compare the efficacy of IDHi to other therapies in treating IDHMT AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

T cell extrinsic mechanics explaining the T cell hyperactivation seen in Activated PI3K δ Syndrome

Abstract Activated PI3K Delta Syndrome (APDS) is a rare condition caused by heterozygous gain of function mutations in PIK3CD, which encodes the leukocyte-restricted p110δ catalytic subunit of phosphoinositol 3-kinase (PI3K). PI3K is activated downstream of many surface receptors expressed by T cells and has been implicated in the control of CD4+ T cell helper differentiation, activation, and proliferation. APDS patients have increased PI3K activity leading to several immune manifestations with the some of the most common features being lymphoproliferation, respiratory tract infections, Th2-related pathologies, and impaired antibody responses. We previously analysed a CRISPR/Cas9 mouse model (Pik3cdE1020K). This showed intrinsic changes impacting on T cell function (increased Th2 cytokines and poor Tfh function) but also extrinsic factors driving a decrease in frequency of naïve and a concurrent increase in memory T cells and Tfh cells, indicating T cell hyperactivation. Here we investigated these extrinsic components further. We found that PI3K B cells are driving Tfh differentiation. We also explored the role of PI3K in maintaining Treg function and identity and determined if Treg dysregulation was driving T cell hyperactivation. These studies reveal an important role of PI3K in modulating T cell differentiation, activation, and function through both T cell intrinsic and extrinsic mechanisms. An improved understanding of T cell hyperactivation can provide insight into the lymphoproliferation that affects most APDS patients. Overall, these results reveal the potential to dissect the mechanisms underlying disease, providing grounds to define new drug targets and ultimately improve the clinical management of these patients.

Developmental defects and impaired network excitability in a cerebral organoid\xa0model of\xa0KCNJ11 p.V59M-related neonatal diabetes

The gene KCNJ11 encodes Kir6.2 a major subunit of the ATP-sensitive potassium channel (KATP) expressed in both the pancreas and brain. Heterozygous gain of function mutations in KCNJ11 can cause neonatal diabetes mellitus (NDM). In addition, many patients exhibit neurological defects ranging from modest learning disorders to severe cognitive dysfunction and seizures. However, it remains unclear to what extent these neurological deficits are due to direct brain-specific activity of mutant KATP. We have generated cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) possessing the KCNJ11 mutation p.Val59Met (V59M) and from non-pathogenic/normal hiPSCs (i.e., control/WT). Control cerebral organoids developed neural networks that could generate stable synchronized bursting neuronal activity whereas those derived from V59M cerebral organoids showed reduced synchronization. Histocytochemical studies revealed a marked reduction in neurons localized to upper cortical layer-like structures in V59M cerebral organoids suggesting dysfunction in the development of cortical neuronal network. Examination of temporal transcriptional profiles of neural stem cell markers revealed an extended window of SOX2 expression in V59M cerebral organoids. Continuous treatment of V59M cerebral organoids with the KATP blocker tolbutamide partially rescued the neurodevelopmental differences. Our study demonstrates the utility of human cerebral organoids as an investigative platform for studying the effects of KCNJ11 mutations on neurophysiological outcome.

Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes.

Phosphoinositide-3-kinase δ (PI3Kδ) is found in immune cells and is part of the PI3K/AKT/mTOR/S6K signalling pathway essential to cell survival, growth and differentiation. Hyperactivation of PI3Kδ enzyme results in Activated PI3-kinase delta syndrome (APDS). This childhood onset, autosomal dominant, combined immunodeficiency, is caused by heterozygous gain of function (GOF) mutations in PIK3CD (encodes PI3Kδ catalytic subunit p110δ), mutations in PIK3R1 (encodes PI3Kδ regulatory subunit p85α) or LOF mutations in PTEN (terminates PI3Kδ signalling) leading to APDS1, APDS2 and APDS-Like (APDS-L), respectively. APDS was initially described in 2013 and over 285 cases have now been reported. Prompt diagnosis of APDS is beneficial as targeted pharmacological therapies such as sirolimus and potentially PI3Kδ inhibitors can be administered. In this review, we provide an update on the clinical and laboratory features of this primary immunodeficiency. We discuss the common manifestations such as sinopulmonary infections, bronchiectasis, lymphoproliferation, susceptibility to herpesvirus, malignancy, as well as more rare non-immune features such as short stature and neurodevelopmental abnormalities. Laboratory characteristics, such as antibody deficiency and B cell and T cell, phenotypes are also summarised.

T cell dysfunction in Activated PI3K δ Syndrome explained by cell intrinsic and extrinsic components

Abstract Activated PI3K Delta Syndrome (APDS) is a rare condition caused by heterozygous gain of function mutations in PIK3CD, which encodes the leukocyte-restricted p110δ catalytic subunit of phosphoinositol 3-kinase (PI3K). PI3K is activated downstream of many T cell receptors and has been implicated in the control of CD4+ T cell helper differentiation, activation and proliferation. APDS patients have increased PI3K activity that leads to several immune manifestations including lymphoproliferation, Th2-related pathologies and impaired Ab responses. Analysis of a CRISPR/Cas9 mouse model (Pik3cdE1020K) showed a decreased frequency of naïve and a concurrent increase in memory T cells and Tfh cells, indicating T cell hyperactivation, as well as changes in cytokine expression and T cell help. Our studies investigated CD4+ T cell intrinsic and extrinsic alterations contributing to the dysregulation of the immune response. We identified cell intrinsic features resulting in increased IL-4 and IL-5, explaining the Th2 mediated disease in these patients. Additionally, cell intrinsic changes in Tfh generation and function were shown in the in vivo mouse model, contributing to an impaired ability to sustain GCs and alter isotype switching. Furthermore, additional studies have shown that the overactive T cells result from both intrinsic and extrinsic factors, with contributions from both dysregulated T cells and B cells exerting effects on T cell activation. Together, these studies reveals an important role of PI3K in modulating T cell differentiation and function through both T cell-intrinsic and extrinsic mechanisms. This provides new insights into the APDS pathophysiology with potential to improve the clinical management of these patients.

Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty

BackgroundProkineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2.MethodsWe analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD).ResultsNo rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD).ConclusionsAs for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

Type I interferon-independent T cell impairment in a Tmem173 N153S/WT mouse model of STING associated vasculopathy with onset in infancy (SAVI)

STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by heterozygous gain of function mutations of STING (stimulator of interferon genes) that had initially been classified as a type I interferonopathy. We recently reported a genetically engineered mouse strain carrying a common SAVI-associated STING mutation. These STING N153S/WT mice reproduce key features of SAVI, including lung inflammation, loss of T cells in spleen and blood, splenomegaly and thymic hypoplasia. Here we show that αβ T lymphocytopenia is due to disrupted T cell development and is associated with impaired T cell activation and a relative increase in γδ T cell numbers. These alterations were not rescued by additional knockout of the type I IFN receptor (IFNAR1). Collectively, our findings consolidate the concept that constitutive STING signalling leads to a SCID-like phenotype in STING N153S/WT mice.

Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.

Cerebellar involvement in warts Hypogammaglobulinemia immunodeficiency myelokathexis patients: neuroimaging and clinical findings

BackgroundWarts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies.Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing.ResultsIn order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8–51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6).ConclusionsTaken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.

Mutated zinc finger protein of the cerebellum 1 leads to microcephaly, cortical malformation, callosal agenesis, cerebellar dysplasia, tethered cord and scoliosis

Heterozygous gain of function mutations in the ZIC1 gene have been described with syndromic craniosynostosis, variable cerebral or cerebellar abnormalities and mild to moderate developmental delay. Deletion of chromosome 3q25.1 including both adjacent ZIC1 and ZIC4 genes have been described as a cause of variable cerebellar abnormalities including Dandy-Walker malformation.We report two siblings presenting with neonatal microcephaly, agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, cerebellar and pons hypoplasia, scoliosis and tethered cord (closed neural tube defect). One of the siblings had apparent partial rhombencephalosynapsis. Trio analysis of exome sequencing data revealed a novel heterozygous frameshift mutation in ZIC1 at the end of exon 3 in one sibling and was confirmed by Sanger sequencing in both children. The mutation was not detected in DNA of both parents, which suggests parental gonadal mosaicism. We show that expression of the mutant allele leads to synthesis of a stable abnormal transcript in patient cells, without evidence for nonsense-mediated decay. Craniosynostosis was not present at birth, which explains why ZIC1 mutations were not initially considered. This severe brain malformation indicates that premature closure of sutures can be independent of the abnormal brain development in subjects with pathogenic variants in ZIC1.

Anterior segment and corneal biomechanics of achondroplasia patients

Herein the anterior segment findings with Pentacam and corneal biomechanics with Ocular Response Analyser of 4 genetically proven cases of achondroplasia are reported. Four patients with heterozygous gain of function p.G380R mutation in fibroblast growth factor Receptor 3 (FGFR3) gene were evaluated. Central corneal thickness was higher than normal in both eyes of one patient, and corneal hysteresis and corneal resistance factor was lower in three eyes of two patients with accompanying high intraocular pressure readings. As a result, the affection of FGFR3 in achondroplasia patients might cause changes in central corneal thickness, corneal hysteresis and corneal resistance factor.

Primary Antibody Deficiencies: Scientific Discoveries Leading to Challenging Paradigms in a Complex Disease Landscape

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies in humans that affect both children and adults. The patients display a decrease in IgG and/or IgA serum levels associated with lower, normal or higher IgM levels, which cause an increased susceptibility to bacterial but also viral infections. Main other complications are auto-immunity, lymphoproliferation and increased susceptibility to various types of cancers. PADs can be caused by B intrinsic and/or extrinsic defects leading to impaired early B cell development, B cell migration, B cell survival, B cell activation or defects in Immunoglobulin class switch recombination (CSR). Among the latter (B cell activation- and CSR-deficiencies), some PADs are linked to unbalanced signaling pathways, in which both gain of function and loss of function variations lead to different immune defects, pinpointing the requirement of a tightly controlled activity for proper immune response.1) Activated PI3K-d Syndromes (APDS) are due to dominant mutations in either the PIK3CD gene encoding the p110d protein, the catalytic subunit of phosphoinositide 3 kinase d (PI3Kd) or the PIK3R1 gene encoding the regulatory subunit of phosphoinositide 3 kinase p85a. Both gene defects lead to hyperactivation of PI3K through an increased p110δ function. A frequent hyper-IgM phenotype is observed, likely due to both a T and a B cell defect. Of note, impaired or loss of function of p110δ or p85α subunit of PI3K leads to a completely different phenotype characterized by an autosomal recessive agammaglobulinemia. The main life-threatening complication of APDS is B lymphoma occurrence. Targeted therapy aiming to decrease PI3K activation is currently on trial.2) The importance of the canonical NF-kB signaling for B cell function was firstly highlighted by the description that missense hemizygous mutations in the IKBKG gene, encoding NEMO, the NF-kB essential modulator, cause an X-linked CSR-deficiency associated with hyphohydrotic ectodermal dysplasia. Recently, heterozygous mutations in either the NFKB1 or the NFKB2 genes (encoding respectively for p105 processed to p50 and p100 processed to p52), have been reported to be causative for common variable immunodeficiency (CVID) due to haploinsufficiency of NF-êkB1 (p52) or NF-kB2 (p50), with less nuclear NF-kB accumulation and less transcriptional regulation. Some carriers are asymptomatic, pinpointing to incomplete penetrance, that suggests the role of gene modifyers or environmental factors. Although NF-κB1-deficiency affects mostly B cells, NF-kB2- deficiency combines a T, B and NK cell defect and is frequently associated to pituitary hormone deficiency.CARD11 (caspase recruitment domain containing protein 11)-deficiency (caused by loss of function bi-allelic mutations) also indicated the importance of CARD11 mediated canonical NF-kB1 signaling for B and T cell function since CARD11-deficient patients have a CVID phenotype. Interestingly, heterozygous gain of function mutations in CARD 11 lead to a different phenotype, the so-called BENTA syndrome (“B cell expansion with NF-kB and T cell anergy”) characterized by B cell lymphocytosis, lymphoproliferation and immunodeficiency.These examples of PADs show that gain of function, haploinsufficiencies and loss of function mutations can be deleterious by disturbing the delicate balance required for adequate signaling pathways during the immune response. DisclosuresNo relevant conflicts of interest to declare.

Follicular thyroid carcinoma due to a heterozygous gain of function mutation in thyrotropin receptor (TSHR)

Follicular thyroid carcinoma due to a heterozygous gain of function mutation in thyrotropin receptor (TSHR)

Early diagnosis of PI3Kδ syndrome in a 2 years old girl with recurrent otitis and enlarged spleen

Heterozygous gain of function mutations in the gene encoding p110δ subunit of PI3K have been recently associated with activated PI3K-δ syndrome (APDS), a novel combined immune deficiency characterized by recurrent sinopulmonary infections, lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma.Here we report a dominant gain of function PIK3CD mutation (E1021K) in a patient presenting with recurrent otitis media, massive splenomegaly, and persistent EBV-viraemia. The immunological studies showed low IgA level, but normal IgM, IgG, and normal antibody response to diphtheria and tetanus toxoid vaccination. Analysis of B lymphocyte subsets revealed abnormal expansion of transitional B cells, and low percentage of switched CD27+IgD− and CD27+IgD+ memory B cells. Analysis of T cell compartment unveiled prevalence of terminally differentiated cells.This study suggests that PIK3CD gain of function mutations should be suspected despite incomplete phenotype in patients with early onset splenomegaly, persistent EBV viremia and abnormal B and T cell subsets despite normal IgG levels. Currently the optimal treatment is still debated, but prompt management can hopefully diminish incidence of severe long-lasting sequelae (i.e. bronchiectasis, ear and sinus damage).

Voltage-gated sodium channel mutations and painful neuropathy: Na(v)1.9 joins the family.

In its simplest terms neuropathic pain arises as a consequence of hyperexcitability within the somatosensory nervous system. It is not surprising therefore that voltage-gated sodium channels (VGSCs), with their key role in regulating neuronal excitability, have come to the fore as pathophysiological factors in human neuropathic pain states. Not only can mutations in these ion channels lead to altered impulse generation/conduction in sensory neurons but they may also lead to degeneration of axon terminals. The VGSC family of proteins has nine members, of which Nav1.7, Nav1.8 and Nav1.9 (encoded by the genes SCN9A , SCN 10A and SCN 11A , respectively) are preferentially expressed in peripheral neurons (Eijkelkamp et al. , 2012). While gain of function variants of Nav1.7 and Nav1.8 have previously been reported in patients with painful peripheral neuropathy, in this issue of Brain , Huang et al. (2014) present the first evidence for a causative role of missense mutations in Nav1.9 in painful neuropathy. The biophysical properties and distribution of Nav1.7, Nav1.8 and Nav1.9 regulate key aspects of nociceptor function. Nav1.7 is likely to be an important determinant of threshold for excitation in nociceptor terminals and may also regulate neurotransmitter release at the central terminals of nociceptors. Homozygous, loss of function mutations in Nav1.7 result in congenital inability to experience pain and anosmia in man, whereas heterozygous gain of function mutations have been linked to the distinct clinical pain syndromes of inherited erythromelalgia (IEM: pain and erythema exacerbated by warming), paroxysmal extreme pain disorder (PEPD: proximal pain and autonomic features in ocular/mandibular and sacral regions), and small fibre neuropathy [SFN: degeneration of small diameter sensory and autonomic axons usually presenting with severe burning pain in …