Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I

Silicone implant-based augmentation rhinoplasty or mammoplasty induces capsular contracture, which has been acknowledged as a process that develops an abnormal fibrotic capsule associated with the immune response to allogeneic materials. However, the signaling pathways leading to the nasal fibrosis remain poorly investigated. We aimed to explore the molecular mechanism underlying the pathogenesis of nasal capsular contracture, with a specific research interest in the signaling pathways involved in fibrotic development at the advanced stage of contracture. By examining our recently obtained RNA sequencing data and global gene expression profiling between grade II and grade IV nasal capsular tissues, we found that both the RAP1 and JAK/STAT signaling pathways were hyperactive in the contracted capsules. This was verified on quantitative real-time PCR which demonstrated upregulation of most of the representative component signatures in these pathways. Loss-of-function assays through siRNA-mediated Rap1 silencing and/or small molecule-directed inhibition of JAK/STAT pathway in ex vivo primary nasal fibroblasts caused a series of dramatic behavioral and functional changes, including decreased cell viability, increased apoptosis, reduced secretion of proinflammatory cytokines, and synthesis of type I collagen, compared to control cells, and indicating the essential role of the RAP1 and JAK/STAT signaling pathways in nasal capsular fibrosis. Our results sheds light on targeting downstream signaling pathways for the prevention and therapy of silicone implant-induced nasal capsular contracture.

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Early-Onset Osteoporosis

Calcified Tissue International ◽

10.1007/s00223-021-00885-6 ◽

2021 ◽

Author(s):

Outi Mäkitie ◽

M. Carola Zillikens

Keyword(s):

Young Adults ◽

Early Onset ◽

Type I Collagen ◽

Young Patients ◽

Fragility Fractures ◽

Underlying Disease ◽

Bone Fragility ◽

Sphingolipid Metabolism ◽

Type I ◽

Loss Of Function

AbstractOsteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

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Functional IRF3 deficiency in a patient with herpes simplex encephalitis

Journal of Experimental Medicine ◽

10.1084/jem.20142274 ◽

2015 ◽

Vol 212 (9) ◽

pp. 1371-1379 ◽

Cited By ~ 98

Author(s):

Line Lykke Andersen ◽

Nanna Mørk ◽

Line S. Reinert ◽

Emil Kofod-Olsen ◽

Ryo Narita ◽

...

Keyword(s):

Herpes Simplex ◽

Autosomal Dominant ◽

Viral Infections ◽

Herpes Simplex Encephalitis ◽

Type I ◽

Toll Like Receptor ◽

Loss Of Function ◽

Impaired Ability ◽

Increased Susceptibility ◽

Hsv 1

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3–TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans.

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Mucopolysaccharidosis type I - Clinical and genetic characteristics of Romanian patients

Revista Romana de Medicina de Laborator ◽

10.2478/rrlm-2020-0030 ◽

2020 ◽

Vol 28 (3) ◽

pp. 279-286

Author(s):

Camelia Alkhzouz ◽

Cecilia Lazea ◽

Diana Miclea ◽

Carmen Asavoaie ◽

Ioana Nascu ◽

...

Keyword(s):

Severe Form ◽

The Other ◽

Compound Heterozygous ◽

Type I ◽

Ophthalmological Examination ◽

Mucopolysaccharidosis Type ◽

Hurler Syndrome ◽

Mucopolysaccharidosis Type I ◽

Genetic Characteristics ◽

Mps I

AbstractBackground: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of α-L-iduronidase (IDUA), which leads to the accumulation of partially digested glycosaminoglycans (dermatan sulfate and heparan sulfate) in the lysosomes and induces multisystemic alteration. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I. To date, more than 290 IDUA mutations have been reported. The purpose of this study was to present the clinical and genetic characteristics of Romanian MPS I syndrome patients and their genotype-phenotype correlation.Patients and methods: Seven patients (5 girls and 2 boys) with MPS type I, belonging to 4 unrelated families, aged 0,75-17.9 years, were enrolled. The study methods consisted in: clinical and standard auxological assessment, bone radiographs, joint ultrasonography, goniometry, neurological and psychological evaluation, hepatic and splenic ultrasonography, cardiological evaluation, otorhinolaryngology examination, ophthalmological examination, spirometry, α-L-iduronidase enzyme activity assay and molecular analysis.Results: The seven patients originated from 4 unrelated families, three patients with severe, two patients with intermediate and two with attenuated clinical phenotype. Each patient presented the classical picture of MPS type I picture, represented by: variable coarse facial features, arthropathy, hepatosplenomegaly, cardiac involvement, respiratory dysfunction and neurological impairment. Five patological variants, three point mutations (p.Q70 *, p.I238Q and p.K324R), two deletion c.1045_1047delGAC, c.46_57delTCGCTCCTG) and an insertion (c.1389 insC) were identified in both alleles of the ADUA gene in homozygous or heterozygous form. Two novel mutations (p.K324R and c.1389 insC) were reported. The p.Q70*(c.208C>T) variant was identified in 2 families with severe form of disease (Hurler syndrome) in homozygous status in one family and in compound heterozygous status in the other family.Conclusion: The p.Q70* missense variant was the most frequent, correlated in all the cases who presented it with severe form, Hurler syndrome, the other mutations being usually isolated and particular for each patient, associated in our patients with less severe MPS I phenotype, as Hurler-Scheie or Scheie syndrome. The results of this study indicated the mutational heterogeneity of the IDUA gene and the difficulty to indicate some correlation between the genotype and phenotype in MPS I patients.

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3P-0797 Lipoprotein lipase Val200Phe: a new loss of function mutation associated with type I hyperlipoproteinemia

Atherosclerosis Supplements ◽

10.1016/s1567-5688(03)91015-4 ◽

2003 ◽

Vol 4 (2) ◽

pp. 236

Author(s):

M.M. Hoffmann ◽

A. Schwentek ◽

N. Vohl ◽

P. Von Blankenburg ◽

H. Wieland

Keyword(s):

Lipoprotein Lipase ◽

Type I ◽

Loss Of Function

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The Effects of Aging and Training on Skeletal Muscle

The American Journal of Sports Medicine ◽

10.1177/03635465980260042401 ◽

1998 ◽

Vol 26 (4) ◽

pp. 598-602 ◽

Cited By ~ 130

Author(s):

Donald T. Kirkendall ◽

William E. Garrett

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Function ◽

Cellular Level ◽

Type I ◽

Loss Of Function ◽

Skeletal Muscle Function ◽

Cross Sectional ◽

Age Related ◽

General Slowing

Aging results in a gradual loss of muscle function, and there are predictable age-related alterations in skeletal muscle function. The typical adult will lose muscle mass with age; the loss varies according to sex and the level of muscle activity. At the cellular level, muscles loose both cross-sectional area and fiber numbers, with type II muscle fibers being the most affected by aging. Some denervation of fibers may occur. The combination of these factors leads to an increased percentage of type I fibers in older adults. Metabolically, the glycolytic enzymes seem to be little affected by aging, but the aerobic enzymes appear to decline with age. Aged skeletal muscle produces less force and there is a general “slowing” of the mechanical characteristics of muscle. However, neither reduced muscle demand nor the subsequent loss of function is inevitable with aging. These losses can be minimized or even reversed with training. Endurance training can improve the aerobic capacity of muscle, and resistance training can improve central nervous system recruitment of muscle and increase muscle mass. Therefore, physical activity throughout life is encouraged to prevent much of the age-related impact on skeletal muscle.

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Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply

Journal of Clinical Investigation ◽

10.1172/jci152475 ◽

2021 ◽

Author(s):

Gundula Povysil ◽

Guillaume Butler-Laporte ◽

Ali G. Gharavi ◽

J. Brent Richards ◽

David B. Goldstein ◽

...

Keyword(s):

Type I ◽

Type I Ifn ◽

Loss Of Function

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IMMU-34. ATRX MUTATIONS PREDICT RESPONSE TO INNATE BASED THERAPY IN GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.526 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi126-vi126

Author(s):

Michelle Bowie ◽

Seethalakshmi Hariharan ◽

Janell Hostettler ◽

Kristen Roso ◽

Yiping He ◽

...

Keyword(s):

Cell Lines ◽

Glioma Cell ◽

Innate Immune ◽

Type I ◽

Loss Of Function ◽

Who Grade ◽

Immune Signaling ◽

Innate Immune Signaling ◽

Recurrent Mutations ◽

Glioma Cell Lines

Abstract BACKGROUND Innate based immunotherapies are becoming increasingly important for treating brain tumor patients. Gliomas carry recurrent mutations in regulatory genes that control innate immune signaling responses. About 71% of adult WHO grade II and III gliomas and 57% of secondary glioblastomas also carry a loss-of-function mutation in the ATRX gene. ATRX is a SWI-SNF chromatin remodeling protein that has major roles in processes such as cell cycle regulation and maintenance of genomic stability. Recent studies have implicated ATRX in dysfunctional innate immune signaling in cancer cells. However, the role of ATRX in mediating innate immune responses has not been investigated in gliomas. METHODS AND RESULTS Human and mouse glioma cell lines from a variety of genetic contexts have been examined including models which carry IDH/ATRX mutations, IDH 1p-/19q- and ATRX -/- status. Additionally, using Crispr-Cas9 technology and cloning cell lines with ATRX deletions, we have derived a series of immune competent and nude mice models. Treating these cell lines with double-stranded RNA based innate stimuli led to an enhanced early induction in phospho-interferon regulatory factor 3 (IRF3) and late induction in phospho-STAT1 in the ATRX knockout (KO) cell lines. A differential increase in interferon-stimulated gene 15 (ISG15) release was also noted in the ATRX KO cell lines, further suggesting that ATRX deletion may enable a potent activation of type I interferon production. A combination of patient-derived glioma cell lines in xenograft models and syngeneic murine glioma models derived from ATRX KO cell lines and controls confirm a survival advantage in both immuno-competent mice and xenografts. Our models are under evaluation with PVSRIPO and other innate based RNA therapies. CONCLUSION Our data suggests that ATRX mutations may confer sensitivity to RNA-based innate immune signaling agonists in gliomas. This potential vulnerability can be targeted in future therapies.

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Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL

Genes ◽

10.3390/genes11111325 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1325

Author(s):

Nurun Nahar Borna ◽

Yoshihito Kishita ◽

Norio Sakai ◽

Yusuke Hamada ◽

Koji Kamagata ◽

...

Keyword(s):

Brain Mri ◽

Leigh Syndrome ◽

Rare Condition ◽

Psychomotor Retardation ◽

Dorsal Column ◽

Severe Form ◽

Cerebral White Matter ◽

Nadh:Ubiquinone Oxidoreductase ◽

Loss Of Function ◽

Radiological Features

Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C > T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.

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