Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short ...stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients. In this study we screened 135 unrelated patients with the clinical diagnosis of CCD for RUNX2 mutations by sequencing analysis and demonstrated 82 mutations 48 of which were novel. By quantitative PCR we screened the remaining 53 unrelated patients for copy number variations in the RUNX2 gene. Heterozygous deletions of different size were identified in 13 patients, and a duplication of the exons 1 to 4 of the RUNX2 gene in one patient. Thus, heterozygous deletions or duplications affecting the RUNX2 gene may be present in about 10% of all patients with a clinical diagnosis of CCD which corresponds to 26% of individuals with normal results on sequencing analysis. We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation.
OBJECTIVE: To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the ...genotype-phenotype correlation. RESEARCH DESIGN AND METHODS: The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA₁c during childhood and adolescence of less-than or equal to7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes. RESULTS: WSD was diagnosed earlier than type 1 diabetes (5.4 ± 3.8 vs. 7.9 ± 4.2 years; P < 0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P = 0.049). Mean duration of remission in WSD was 2.3 ± 2.4 vs. 1.6 ± 2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P < 0.001). Neurologic disease progression was faster in the WSD group with a mean HbA₁c >7.5% (P = 0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P = 0.028). CONCLUSIONS: Endoplasmic reticulum stress-mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.
Abstract
Next-generation sequencing is increasingly applied during the diagnostic work-up of patients with bleeding diathesis and has facilitated the diagnosis of rare bleeding disorders such as ...inherited platelet function disorders. Mutations in RAS guanyl releasing protein 2 (RasGRP2), also known as calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), underlie a recently described platelet signal transduction abnormality. Here we present the case of a consanguineous family originating from Afghanistan with two siblings affected by recurrent severe mucocutaneous bleedings. Platelet function testing demonstrated a marked reduction of aggregation induced by collagen and adenosine diphosphate. Whole exome sequencing revealed a novel homozygous nonsense
RASGRP2
mutation segregating with the bleeding disorder in the family.
The hypodactylous (hd) locus impairs limb development and spermatogenesis, leading to male infertility in rats. We show that the hd mutation is caused by an insertion of an endogenous retrovirus into ...intron 10 of the Cntrob gene. The retroviral insertion in hd mutant rats disrupts the normal splicing of Cntrob transcripts and results in the expression of a truncated protein. During the final phase of spermiogenesis, centrobin localizes to the manchette, centrosome, and the marginal ring of the spermatid acroplaxome, where it interacts with keratin 5-containing intermediate filaments. Mutant spermatids show a defective acroplaxome marginal ring and separation of the centrosome from its normal attachment site of the nucleus. This separation correlates with a disruption of head-tail coupling apparatus, leading to spermatid decapitation during the final step of spermiogenesis and the absence of sperm in the epididymis. Cntrob may represent a novel candidate gene for presently unexplained hereditary forms of teratozoospermia and the "easily decapitated sperm syndrome" in humans.
IMPORTANCE: Familial chilblain lupus is a monogenic autosomal dominant form of cutaneous lupus erythematosus that in most cases is caused by mutations in the 3 prime repair exonuclease 1 (TREX1). ...Familial chilblain lupus presents in early childhood with cold-induced painful erythematous infiltrates leading to mutilation and is associated with systemic involvement illustrated by an elevated type I interferon (IFN) signature in the skin and blood. Effective treatment is currently not available. OBJECTIVES: To evaluate the clinical response to the Janus kinase inhibitor baricitinib in familial chilblain lupus and assess the effect of cold on patient fibroblasts. DESIGN, SETTING, AND PARTICIPANTS: In this case series, 3 patients with familial chilblain lupus due to TREX1 mutation underwent treatment with baricitinib for 3 months. INTERVENTIONS: Doses of baricitinib, 4 mg, were administered daily for 3 months. MAIN OUTCOMES AND MEASURES: Reduction of cutaneous lupus lesions was measured by the revised cutaneous lupus area and severity index, pain due to skin and joint involvement was assessed by visual analog scale, type I IFN signature in blood was determined by polymerase chain reaction, and the in vitro response of fibroblasts to cold exposure was analyzed. RESULTS: All 3 patients (2 women and 1 man; mean SD age, 51 24 years) showed a significant improvement of cutaneous lupus lesions with suppression of systemic type I IFN activation. One patient had a complete remission regarding pain and, in 2 patients, pain associated with joint inflammation was partially reduced. No severe adverse reactions were reported. Exposure of patient fibroblasts to cold induced a stress response and enhanced senescence along with induction of IFN-stimulated gene in vitro. CONCLUSIONS AND RELEVANCE: These findings demonstrate the therapeutic efficacy of Janus kinase inhibition in a monogenic form of lupus among 3 patients and provide mechanistic insight into the process of disease exacerbation by cold in TREX1-deficient cells. This finding may be relevant to other type I IFN–mediated disorders and implicates Janus kinase inhibition as a potential therapeutic option also for multifactorial cutaneous lupus erythematosus.
BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify ...diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator NEMO), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
Zusammenfassung
Autoinflammatorische Erkrankungen umfassen eine immer größer werdende, genetisch heterogene Gruppe von Erkrankungen mit breitem und variablem klinischen Spektrum. Aus nosologischer ...Perspektive wird eine strikte Abgrenzung der Autoinflammation von Autoimmunität und Immundefizienz dem aktuellen Kenntnisstand zu pathogenetischen Mechanismen nicht gerecht. Daher erscheint eine systembasierte Einteilung, die sich an den in die inflammatorischen Prozesse involvierten Signalwegen orientiert, auch im Hinblick auf das klinische Management sinnvoll. So sprechen die Inflammasomopathien in vielen Fällen auf eine Blockade des Interleukin(IL)-1β an, während die Typ-1-Interferonopathien einer Therapie mithilfe der Januskinase(JAK)-Inhibition zugänglich sind.
Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN signaling is activated by pattern recognition receptors upon sensing of viral nucleic acids ...and induces antiviral programs through modulation of innate and adaptive immune responses. Type I interferonopathies comprise a heterogenous group of genetically determined diseases that are characterized by inappropriate activation of type I IFN. While their phenotypic spectrum is broad, ranging from severe neurological impairment to mild cutaneous disease, systemic autoinflammation, and autoimmunity are commonly shared signs of type I interferonopathies. Although the mechanisms underlying various disease phenotypes associated with inappropriate type I IFN activation have yet to be fully elucidated, our current understanding of the molecular pathogenesis of type I interferonopathies has provided a set of candidate molecules that can be interrogated in search of targeted therapies.
Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial ...dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.
The aspartyl protease renin catalyzes the initial and rate-limiting step in the formation of the biologically active peptide angiotensin II. It is mainly synthesized in the kidney as a preprohormone ...and secreted via constitutive and regulated pathways. We identified a novel transcript of the rat renin gene, renin b, characterized by the presence of an alternative first exon (exon 1b) that is spliced to exon 2 of the known transcript, termed renin a. We demonstrated that renin b is exclusively expressed in the brain. In contrast, renin a was not expressed in the brain. Using primer extension assays, we mapped the transcriptional start site of this novel mRNA within intron 1 of the rat genomic sequence, suggesting the presence of a brain-specific promoter within intron 1. The presence of a brain-specific renin isoform is evolutionally conserved, as demonstrated by the finding of renin b isoforms in mice and humans. The predicted protein renin b lacks the prefragment as well as a significant portion of the profragment and is therefore predicted not to be a secreted protein, unlike the classically described isoform renin a. As shown by in vitro translation of full-length renin b mRNA in the presence of microsomal membranes, renin b was not targeted into the endoplasmatic reticulum and remained intracellularly in transiently transfected AtT-20 cells. These findings provide evidence for a novel pathway of intracellular angiotensin generation that occurs exclusively in the brain. (Circ Res. 1999;84:240-246.)
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