Connective Tissue Abnormalities Research Articles

Successful Spinal Anesthesia for Cesarean Section in a Patient With Marfan Syndrome Complicated by Dural Ectasia

(Int J Obstet Anesth. 2018;35:88–92) Marfan syndrome (MFS) is an autosomal dominant condition characterized by connective tissue abnormalities across multiple systems. Patients with MFS may have a dilated aortic root, and this can place the parturient at increased risk during labor and delivery. Cesarean delivery is sometimes recommended for women with MFS who have an aortic root diameter >40 mm. However, reduced effectiveness of spinal anesthesia has been reported in some patients with MFS. The failure is thought to possibly be related to the dural ectasia that is present in many patients with MFS; this may lead to incomplete cephalad distribution of intrathecal local anesthetic. This case report detailed a parturient who was undergoing her second cesarean delivery after failed neuraxial anesthesia during her first delivery, with the author postulating that warmed isobaric bupivacaine, injected as far away as possible from the ectatic dural sac, may be able to overcome inconsistent intrathecal distribution.

Report of a novel ATP7A mutation causing distal motor neuropathy

We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients’ blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

Muscle and joint function in children living with arthrogryposis multiplex congenita: A scoping review.

Arthrogryposis multiplex congenita (AMC) is characterized by congenital joint contractures present in two or more body areas. Lack of fetal movement is the underlying cause of AMC, which can lead to abnormal connective tissue surrounding the joint resulting in stiffness and muscle atrophy. Treatment aims at improving function and mobility through surgical and/or conservative interventions. A scoping review was conducted to explore the existing knowledge of the evaluation and treatment of muscle and joint function in children with AMC. Three search engines were included and identified 1,271 articles. Eighty-seven studies met the selection criteria and were included in this review. All included studies focused on joints, 30 of which also assessed the muscle. Assessment most often included the position of the contractures (n = 72), as well as range of motion (n = 66). Interventions to improve muscle and joint function were reported in 82 of the 87 papers and included surgery (n = 70) and conservative interventions (n = 74) with bony surgery (i.e., osteotomy) the most common surgery and rehabilitation the most common conservative intervention. Recurrences of contractures were mentioned in 46 of the 68 studies providing a follow-up. Future studies should use validated measures to assess muscle and joint function, and conservative interventions should be described in greater detail and to include a longer follow-up.

The color of skin: yellow diseases of the skin, nails, and mucosa

The colors reflected from the skin are important indicators of dermatologic and systemic disorders. Incident light is subject to absorption by chromophores in the skin and scattering. Chromophores associated with yellow light reflection include the carotenoids and bilirubin. Various pathophysiologic mechanisms associated with these and other chromophores manifest with a yellow hue on examination. This review describes these mechanisms and the clinical features of yellow skin disorders by morphology. A brief summary of the differential diagnosis, laboratory investigations, and treatments are presented. Yellow skin disorders are a heterogenous group composed of abnormalities in keratin, elastic and connective tissue, lipid metabolism, and other states of metabolic, inflammatory, or organ dysfunction. Patients will present through different routes, and skin disease may precede or follow systemic disease. Dermatologists have an essential role in identifying those with malignant or systemic associations to ensure early diagnosis and treatment.

Mechanism of action of celastrol against rheumatoid arthritis: A network pharmacology analysis

Network pharmacology uses bioinformatics to broaden our understanding of drug actions and thereby to advance drug discovery. Here we apply network pharmacology to generate testable hypotheses about the multi-target mechanism of celastrol against rheumatoid arthritis. We reconstructed drug–target pathways and networks to predict the likely protein targets of celastrol and the main interactions between those targets and the drug. Then we validated our predictions of four candidate targets (IKK-β, JNK, COX-2, MEK1) by performing docking studies with celastrol. The results suggest that celastrol acts against rheumatoid arthritis by regulating the function of several signaling proteins, including MMP-9, COX-2, c-Myc, TGF-β, c-JUN, JAK-1, JAK-3, IKK-β, SYK, MMP-3, JNK and MEK1, which regulate the functions of Th1 and Th2 cells, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Celastrol is predicted to affect networks involved mainly in cancer, connective tissue disorders, organismal injury and abnormalities, tissue development, cell death and survival. This network pharmacology strategy may be useful for discovery of multi-target drugs against complex diseases.

Human Marfan and Marfan-like Syndrome associated mutations lead to altered trafficking of the Type II TGFβ receptor in Caenorhabditis elegans.

The transforming growth factor-β (TGFβ) family plays an important role in many developmental processes and when mutated often contributes to various diseases. Marfan syndrome is a genetic disease with an occurrence of approximately 1 in 5,000. The disease is caused by mutations in fibrillin, which lead to an increase in TGFβ ligand activity, resulting in abnormalities of connective tissues which can be life-threatening. Mutations in other components of TGFβ signaling (receptors, Smads, Schnurri) lead to similar diseases with attenuated phenotypes relative to Marfan syndrome. In particular, mutations in TGFβ receptors, most of which are clustered at the C-terminal end, result in Marfan-like (MFS-like) syndromes. Even though it was assumed that many of these receptor mutations would reduce or eliminate signaling, in many cases signaling is active. From our previous studies on receptor trafficking in C. elegans, we noticed that many of these receptor mutations that lead to Marfan-like syndromes overlap with mutations that cause mis-trafficking of the receptor, suggesting a link between Marfan-like syndromes and TGFβ receptor trafficking. To test this hypothesis, we introduced three of these key MFS and MFS-like mutations into the C. elegans TGFβ receptor and asked if receptor trafficking is altered. We find that in every case studied, mutated receptors mislocalize to the apical surface rather than basolateral surface of the polarized intestinal cells. Further, we find that these mutations result in longer animals, a phenotype due to over-stimulation of the nematode TGFβ pathway and, importantly, indicating that function of the receptor is not abrogated in these mutants. Our nematode models of Marfan syndrome suggest that MFS and MFS-like mutations in the type II receptor lead to mis-trafficking of the receptor and possibly provides an explanation for the disease, a phenomenon which might also occur in some cancers that possess the same mutations within the type II receptor (e.g. colon cancer).

Evidence for a de novo, dominant germ-line mutation causative of osteogenesis imperfecta in two Red Angus calves.

A genetic disorder, osteogenesis imperfecta (OI) is broadly characterized by connective tissue abnormalities and bone fragility most commonly attributed to alterations in Type I collagen. Two Red Angus calves by the same sire presented with severe bone and dental fragility, blue sclera, and evidence of in utero fractures consistent with OI congenita. Comparative analyses with human cases suggested the OI in these calves most closely resembled that classified as OI Type II. Due to the phenotypic classification and shared paternity, a dominant, germ-line variant was hypothesized as causative although recessive genotypes were also considered due to a close relationship between the sire and dam of one calf. Whole-genome sequencing revealed the presence of a missense mutation in the alpha 1 chain of collagen Type I (COL1A1), for which both calves were heterozygous. The variant resulted in the substitution of a glycine residue with serine in the triple helical domain of the protein; in this region, glycine normally occupies every third position as is critical for correct formation of the Type I collagen molecule. Allele-specific amplification by droplet digital PCR further quantified the variant at a frequency of nearly 4.4% in the semen of the sire while it wasabsent in his blood, supporting the hypothesis of a de novo causative variant for which the germ line of the sire was mosaic. The identification of novel variants associated with unwanted phenotypes in livestock is critical as the high prolificacy of breeding stock has the potential to rapidly disseminate undesirable variation.

A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function.

Key points Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architectureTNX is associated exclusively with vagal‐afferent endings and some myenteric neurones in mouse and human stomach, respectively.TNX‐deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal‐afferent sensitivity.Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX‐deficient mice.TNX‐deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology.TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents‐baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. Tenascin‐X (TNX) is a glycoprotein that regulates tissue structure via anti‐adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers–Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. Previously, we have shown that TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX‐deficient patients and mice. We aimed to identify whether TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report that TNX was present in calretinin‐immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice, suggesting that vagal afferent responses are probably the result of altered peripheral mechanosensitivity. In TNXB‐deficient patients, significantly greater symptoms of reflux, indigestion and abdominal pain were reported. In the present study, we report the first role for TNX in gastric function. Further studies are required in TNX deficient patients to determine whether symptoms can be relieved using GABAB agonists.

Urological Problems in Patients with Menkes Disease.

BackgroundMenkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic “kinky” hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications.MethodsA total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records.ResultsAll the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up.ConclusionUrologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.

Dysplasie fibreuse et syndrome de McCune-Albright

Fibrous dysplasia of bone (FD) is a rare congenital but not heritable bone disease, that is characterized by the replacement of normal bone structure with abnormal fibro-osseous connective tissue. This disease is caused by activating mutation of GNAS. FD may cause bone pain, bone deformity and fractures. It can affect one bone (monostotic FD) or multiple bones (polyostotic FD). FD may either occur as an isolated condition or as part of the McCune-Albright syndrome (MAS), which is characterized by the following triad: FD, hyperfunctioning endocrinopathies (mainly peripheral precocious puberty), and/or café-au-lait spots. Diagnosis relies on bone imaging and if necessary on pathological examination on bone biopsy with GNAS mutation search. The prognosis is usually good in monostotic disease; polyostotic diseases can lead to bone pain and fractures with significant disabilities. Treatment starts with the management of pain; moreover, various uncontrolled studies have shown the interest of bisphosphonates on bone pain but probably also on the improvement of radiological images; a randomized placebo-controlled study did not demonstrate the efficacy of oral bisphosphonates so the preferred route is intravenous. Other therapeutics are being studied (in particular Tocilizumab and Denosumab) but controlled studies are needed. Endocrinological management is of course necessary in cases of McCune-Albright syndrome, especially in cases of precocious puberty. Finally, specialized orthopedic care will be essential for the prevention and treatment of fracture complications.

Periodontal Ehlers\u2013Danlos syndrome is associated with leukoencephalopathy

Here, we report brain white matter alterations in individuals clinically and genetically diagnosed with periodontal Ehlers–Danlos syndrome, a rare disease characterized by premature loss of teeth and connective tissue abnormalities. Eight individuals of two families clinically diagnosed with periodontal Ehlers–Danlos syndrome were included in the present study and underwent general physical, dental, and neurological examination. Whole exome sequencing was performed, and all patients included in the study underwent MRI of the brain. Whole exome sequencing revealed heterozygous C1R mutations c.926G>T (p.Cys309Phe, Family A) and c.149_150TC>AT (p.Val50Asp, Family B). All adult individuals (n = 7; age range 31 to 68 years) investigated by MRI had brain white matter abnormalities. The MRI of one investigated child aged 8 years was normal. The MRI pattern was suggestive of an underlying small vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the neurologic features. Medical history revealed recurrent headaches or depression in some cases. Neurological examination was unremarkable in all individuals but one had mild cognitive decline and ataxia and experienced a seizure. The observation that periodontal Ehlers–Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy opens a new pathogenic link between the classical complement pathway, connective tissue, brain small vessels, and brain white matter abnormalities.

Orthognathic surgery for patients with fibrous dysplasia involved with dentition

BackgroundFibrous dysplasia (FD) is characterized by the replacement of normal bone by abnormal fibro-osseous connective tissue and typically treated with surgical contouring of the dysplastic bone. When dysplastic lesions involve occlusion, not only is surgical debulking needed, orthognathic surgery for correction of dentofacial deformity is mandatory. However, the long-term stability of osteotomized, dysplastic bone segments is a major concern because of insufficient screw-to-bone engagement during surgery and the risk of FD lesion re-growth.Case presentationThis case report reviewed two patients with non-syndromic FD that presented with maxillary occlusal canting and facial asymmetry. Le Fort I osteotomy with recontouring of the dysplastic zygomaticomaxillary region had been performed. The stability of osseous segments were favorable. However, dysplastic, newly formed bone covered the previous plate fixation site and mild bony expansion was observed, which did not influence the facial profile. Including the current cases, 15 cases of orthognathic surgery for FD with dentition have been reported in the literature.ConclusionThe results showed that osteotomy did not appear to significantly reduce the long-term stability of the initial fixation insufficiency of the screw to the dysplastic bone. However, based on our results and those of the others, long-term follow-up and monitoring are needed, even in cases where the osteotomized segment shows stable results.

Fragile X syndrome and connective tissue dysregulation.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and autism spectrum disorders, and it is an X-linked disorder in which there is a deficiency of the fragile X mental retardation 1 protein. This protein is crucial in regulating translation of mRNAs related to dendritic maturation and cognitive development. The phenotype of FXS is characterized by neurobehavioral alterations, social deficits, communication difficulties, and findings which suggest an alteration of connective tissue, especially in the ligaments and muscles, cardiovascular system and genitourinary system. Connective tissue connects and supports all other tissues of the body and is composed of cells and extracellular matrix (ECM). Several proteins have been involved in the connective tissue abnormalities associated with the FXS, such as matrix metalloproteinase 9, which plays an important role in the homeostasis of the ECM, being a potential therapeutic target for certain tetracycline antibiotics that have shown beneficial effects in FXS. Here, we review connective tissue problems described in FXS.

Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency

Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in anchoring fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities, including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility.

Prevalence of rheumatic diseases among city dwellers of Dnestr region of Republic Moldova

It is conducted researches of frequency of rheumatic diseases among 4000 people of the organised and unorganized populations of inhabitants of Tiraspol. On the first place in structure rheumatic diseases is оsttoartrit which relative density makes 60.0%, on the second place - an revmatic arthritis - 7%, on the third place - spondilo arthritis - 6%. The gout - of 5.5%, jet arthritises of 3.0% and system defeats of a connecting fabric - 1.4% Further has settled down. Thus оsteoartrit it was defined with frequency of 10.1% of cases, revmatic arthritis - 0.3%, a gout of 0.22%, jet arthritise arthritis - 0.03%, the spondilo arthritis - 0.04% and system defeats of a connecting fabric - 0.10%, etc. At comparison of the received data about frequency rheumatic diseases in Dnestr region Moldova with the data of similar researches in the Russian Federation have been established that they approximately correspond to the data across the Russian Federation. Besides almost at everythird patient with rheumatic diseases (32.4%) were defined signs abnormal connective tissue , and meteorticulate a syndrome the obtained data allows to put forward the assumption of interrelation rheumatic diseases with, abnormal connective tissue which presence, most likely, causes a spectrum accompanying rheumatic diseases somatic diseases.

Association of Exfoliation Syndrome With Risk of Indirect Inguinal Hernia

Exfoliation syndrome (XFS) is a systemic connective tissue disease, and abnormal connective tissue metabolism is implicated in inguinal hernias (IH). Associating XFS with comorbid conditions may illuminate their underlying pathophysiology and affect clinical screening and treatment. Exfoliation syndrome involves altered systemic extracellular matrix (ECM) homeostasis involving elastin metabolism. Hernias occur owing to abnormal ECM synthesis, metabolism, or repair. Inguinal hernias involve weakening or rupture of the abdominal/groin wall. To determine an association between patients with XFS and patients with IH in Utah, possibly differing between direct or indirect hernia. Cross-sectional study in a large health care system of Utah hospitals and clinics. Conditional logistic regression odds ratios were used to estimate risk of XFS in patients with IH overall and by subtype (direct or indirect) compared with control individuals. Codes specific to direct and indirect IH with additional medical records review of 186 procedures were used to classify IH subtypes that were not prespecified. Bootstrap resampling with jackknife estimation used to calculate 95% confidence intervals. The model accounted for matching on sex and age and adjusted for body mass index and tobacco use. Population-based sample using medical records from 1996 to 2015 that identified 2594 patients 40 years or older on January 1, 1996, with surgical IH repair and 12 966 random control patients with no IH history matched 5:1 on sex and birth year. Data were analyzed between September 10, 2017, and October 23, 2017. Exfoliation syndrome outcome defined by diagnosis codes for XFS or exfoliation glaucoma from 1996 to 2015. Participants were primarily white (2532 of 2594 patients, [96.1%]; 12 454 of 12 966 control individuals [97.6%]) and non-Hispanic (2396 of 2594 patients [92.4%]); 250 participants were women (9.6%). Of study participants, 22 patients with IH and 43 control individuals were diagnosed as having XFS, respectively. Patients with IH had a 2.3-fold risk for an XFS diagnosis compared with control individuals (95% CI, 1.4-3.5; P = .03), and XFS risk with indirect IH appeared especially pronounced. Inguinal hernia was associated with an increased risk of XFS in this Utah population. Further work is needed to understand the pathophysiology, genetics, and environmental factors contributing to both diseases.

Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity

BackgroundSLIT2 is a protein ligand for the Roundabout (ROBO) receptor and was found to play a major role in repulsive midline axon guidance in central nervous system development. Based on studies utilizing knockout models, it has been postulated that SLIT2 is important for preventing inappropriate axonal routing during mammalian optic chiasm development.MethodsCase report.ResultsHere, we report a case of congenital myopia, anisometropia, and obesity in a patient with a SLIT2 point mutation. Examination of the patient’s skin biopsy revealed abnormalities in elastin and collagen fibrils that suggest an underlying connective tissue disorder. Structural modeling placed the novel mutation (p.D1407G) in the EGF-like domain 8 and was predicted to affect interactions with SLIT2 binding partners.ConclusionsTo the authors’ knowledge, this is the first report of a SLIT2 variant in the context of these ocular findings.

Advances in the molecular mechanism and diagnosis and treatment of fragile X syndrome

Fragile X syndrome (FXS) is the most common monogenic disease that causes intellectual disability and autism spectrum disorder (ASD), causing moderate to severe mental retardation with unusual facial features and connective tissue abnormalities. Fragile X syndrome is caused by the mutation of FMR1 gene, resulting in the reduction or loss of its product, fragile X mental retardation protein (FMRP) .The diagnosis is mainly based on the detection of FMR1 gene , and there is no effective treatment for fragile X syndrome. Therefore, it is very important to strengthen genetic counseling and prenatal diagnosis, and effectively reduce the incidence of fragile X syndrome. Key words: Fragile X syndrome/GE/DI/TH; Fragile X mental retardation protein/GE; Prenatal diagnosis

Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities

The natriuretic peptide signaling pathway has been implicated in many cellular processes, including endochondral ossification and bone growth. More precisely, different mutations in the NPR-B receptor and the CNP ligand have been identified in individuals with either short or tall stature. In this study we show that the NPR-C receptor (encoded by NPR3) is also important for the regulation of linear bone growth. We report four individuals, originating from three different families, with a phenotype characterized by tall stature, long digits, and extra epiphyses in the hands and feet. In addition, aortic dilatation was observed in two of these families. In each affected individual,we identified a bi-allelic loss-of-function mutation in NPR3. The missense mutations (c.442T>C [p.Ser148Pro] and c.1088A>T [p.Asp363Val]) resulted in intracellular retention of the NPR-C receptor and absent localization on the plasma membrane, whereas the nonsense mutation (c.1524delC [p.Tyr508∗]) resulted in nonsense-mediated mRNA decay. Biochemical analysis of plasma from two affected and unrelated individuals revealed a reduced NTproNP/NP ratio for all ligands and also high cGMP levels. These data strongly suggest a reduced clearance of natriuretic peptides by the defective NPR-C receptor and consequently increased activity of the NPR-A/B receptors. In conclusion, this study demonstrates that loss-of-function mutations in NPR3 result in increased NPR-A/B signaling activity and cause a phenotype marked by enhanced bone growth and cardiovascular abnormalities.

Human TH9 differentiation is dependent on signal transducer and activator of transcription (STAT) 3 to restrain STAT1-mediated inhibition

Patients with loss-of-function (LOF) signal transducer and activator of transcription 3 (STAT3) mutations have dermatitis, enhanced IgE production despite a relative lack of immediate hypersensitivity, recurrent infection, and an increased rate of lymphoma in addition to a number of skeletal and connective tissue abnormalities. Patients with STAT1 gain-of-function (GOF) mutations also have susceptibility to candidiasis and sinopulmonary infection, as well as autoimmunity and squamous cell carcinoma, in addition to even more broad phenotypes. Because of the link between TH9 cells and allergic inflammation, autoimmunity, and antitumor surveillance and because evidence shows a role for either STAT3 or STAT1 in TH9 differentiation conflicts, we sought to determine the status on this lineage of STAT1 GOF and STAT3 LOF mutations in human subjects. We detected IL-9 levels and TH9 differentiation in patients with STAT3 LOF and STAT1 GOF mutations, together with TH9 transcript factors, and partially rescued their deficiency invitro by adding cytokines they lacked or transfecting key molecules. We found that PBMCs or sorted naive CD4+ T cells from patients with STAT3 LOF and STAT1 GOF mutations had impaired TH9 generation/differentiation. STAT3 inhibition in normal TH9 cultures diminished early IL-21 induction and late IL-9 production, whereas exogenous IL-21 enhanced TH9 differentiation, even with STAT3 inhibition, by restoring suppressor of cytokine signaling 3 expression and thus inhibiting excessive phosphorylated signal transducer and activator of transcription (p-STAT) 1 activation. Furthermore, exogenous expression of suppressor of cytokine signaling 3 or either T-bet or STAT1 RNA interference in STAT3 LOF cells partially rescued IL-9 differentiation. Collectively, these results suggest that human TH9 differentiation depends on normal p-STAT3 and IL-21 production to suppress p-STAT1 activation and T-bet transcription.